All processes that occur before the activation of the zygotic genome at the midblastula transition are driven by maternal products, which are produced during oogenesis and stored in the mature oocyte. Upon egg activation and fertilization, these maternal factors initiate developmental cascades that carry out the embryonic developmental program. Even after the initiation of zygotic gene expression, perduring maternal products continue performing essential functions, either together with other maternal factors or through interactions with newly expressed zygotic products. Advances in zebrafish research have placed this organism in a unique position to contribute to a detailed understanding of the role of maternal factors in early vertebrate development. This review summarizes our knowledge on the processes involved in the production and redistribution of maternal factors during zebrafish oogenesis and early development, as well as our understanding of the function of these factors in axis formation, germ layer and germ cell specification, and other early embryonic processes. Developmental Dynamics, 2003. © 2003 Wiley-Liss, Inc.

INTRODUCTION

In all animals, there is a delay between fertilization and the activation of the zygotic genome, when the embryo relies on gene products present in the egg (maternal factors) and before it begins to use newly synthesized products derived from the embryo itself (zygotic factors). In invertebrates and lower vertebrates, this transitional period lasts many cell cycles, typically until the embryos consist of thousands of cells. Even in mammals, where zygotic genomes are activated at the two-cell stage and maternal factors are thought to be less important, it is likely that maternal cues also direct some aspects of embryonic development (Johnson, 2001).

The activation of the zygotic genome marks a point in development termed the midblastula transition (MBT; Newport and Kirschner, 1982a, b). In zebrafish embryos, this transition occurs gradually throughout a window of approximately 2 hr, starting at cell cycle 10 and ending at late cycle 13, and also involves the transition from a pattern of rapid, synchronous cell divisions to one of longer, asynchronous cell divisions, and, with a one- to two-cell cycle delay, the initiation of cell motility (Kane et al., 1992; Kane and Kimmel, 1993; Zamir et al., 1997). Most of these changes appear to be initiated by reaching a threshold nucleocytoplasmic ratio where the titration of a hypothetical maternally supplied cytoplasmic factor results in transcriptional initiation (Kane and Kimmel, 1993; Zamir et al., 1997).

All processes that occur before zygotic gene activation at MBT must rely on maternal products, which are produced during oogenesis and are present in the egg at the time of fertilization. Such maternal factors must support all basic cellular functions, such as cellular metabolism, nuclear and cellular divisions, and intercellular adhesion (Table 1). Embryologic manipulations and, more recently, molecular analysis indicate that the premidblastula embryo also contains asymmetries in molecules key to the determination of cell fate, even if the morphologic manifestations of these early asymmetries are not apparent until later in embryonic development. Moreover, recent genetic analysis has demonstrated that there is a transitional period in which both maternal and zygotic products, sometimes derived from the same gene, cooperate to carry out developmental processes.

Table 1. Selected Genes with a Maternal Genetic Contributiona

Gene	Type of mutation/reverse genetics method	Molecular identity	Process affected by loss of function	Reference
janus	Recessive, strictly maternal	Unknown	Cell adhesion	Abdelilah et al., 1994
futile cycle	Recessive, strictly maternal	Unknown	Pronuclear fusion, spindle formation	Dekens et al., 2003
nebel	Recessive, strictly maternal	Unknown; required for FMA formation	Cell adhesion, germ plasm segregation	Pelegri et al., 1999
half-baked	Dominant maternal–zygotic	Unknown	Epibolic movements	Kane et al., 1996
yobo	Recessive, strictly maternalb	Unknown	Axis convergence and extension	Odenthal et al., 1996
ichabod	Recessive, strictly maternal	Unknown; required for βcat nuclear accumulation	Dorsal organizer induction	Kelly et al., 2000
radar	MO-mediated knockdown	TGF-β factor	Development of ventral cell fates	Sidi et al., 2003
alk8/lost-a-fin	Recessive, maternal–zygotic/MO-mediated knockdown	Type I TGF-β receptor	Development of ventral cell fates	Mintzer et al., 2001; Bauer et al., 2001
smad5/somitabun	Dominant maternal–zygotic; dominant and recessive maternal	Intracellular factor in TGF-β signaling	Development of ventral cell fates	Mullins et al., 1996; Kramer et al., 2002
sizzled/ogon	Recessive maternal–zygotic	Secreted Frizzled-related factor; feedback inhibitor of Bmp signaling	Development of dorsal cell fates	Miller-Bertoglio, 1999; Wagner and Mullins, 2002; Yabe et al., 2003
tcf-3/headless	Recessive, maternal–zygotic	HMG-box transcription factor	Development of anterior structures	Kim et al., 2000
pbx4/lazarus	Recessive, maternal–zygotic	Homeodomain transcription factor	Hindbrain segmentation and rhombomere identity	Waskiewicz et al., 2002
one eyed pinhead	Recessive, maternal–zygotic	EGF-CFC family coreceptor	Induction of mesendoderm	Gritsman et al., 1999
foxH1/fast1/ schmalspur	Recessive, maternal–zygotic	Forkhead domain transcription factor	Induction of mesendoderm	Pogoda et al., 2000; Sirotkin et al., 2000

a MO, morpholino; FMA, furrow microtubule array.
b Mutations in yobo appear to have a strictly maternal effect on axis convergence and extension. Zygotic homozygosity for yobo also results in a reduction in xanthophores during larval stages.

That maternal factors are crucial for the earliest stages of animal development has been amply demonstrated in model invertebrate systems such as Drosophila (St. Johnston and Nüsslein-Volhard, 1992) and Caenorhabditis elegans (Kemphues and Strome, 1997; Schnabel and Priess, 1997). Molecular and embryologic studies have also demonstrated the importance of maternal factors in early development of lower vertebrates, such as ascidians (Nishida, 2002) and Xenopus (Heasman, 1997). With an MBT period starting at the 1,000-cell stage, it was expected that maternal factors also play a major role in early developmental processes in the zebrafish embryo. However, only in recent years have we obtained concrete molecular genetic evidence to support this notion. This review attempts to summarize the current status of knowledge that is rapidly being acquired in this field.

GENERAL ASPECTS OF FISH OOGENESIS: PRODUCTION AND UPTAKE OF MATERNAL PRODUCTS

In teleost fish, almost all maternal products present in the egg appear to be produced endogenously during oogenesis by the oocyte itself. For a single cell, this is an impressive feat, because a fish oocyte can increase in volume a few hundred-fold, and exhibit RNA and protein content increases of two and three orders of magnitude, respectively (Chaudhuri and Mandal, 1980; Selman et al., 1993). Here, I discuss the main features relevant to the progressive accumulation and storage of maternal products during oogenesis, and the reader is directed to other sources for a more thorough review of this process (Guraya, 1969; Selman et al., 1993).

The first signs of accumulation of maternal products, as evidenced by an increase in volume of the ooplasm, occur during the earliest recognizable stage of oocyte differentiation, the prefollicle stage of the primary growth phase (stage IA; oocyte diameter 7–20 μm; see Selman et al. [1993] for a detailed description of oocyte stages in zebrafish, see Fig. 1 for a schematized diagram showing some of these stages). During this early stage, numerous small nucleoli begin to accumulate in the nucleus and increase in number so that in subsequent stages up to 1,500 nucleoli can be observed at the periphery of the nucleus and in close association with the inner nuclear membrane (Hisaoka and Firlit, 1962; Baumeister, 1976). Although not specifically shown in zebrafish, studies in other fish as well as amphibians suggest that these nucleoli may be involved in the amplification of ribosomal RNAs (Wallace and Selman, 1990).

Details are in the caption following the image — **Figure 1**
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Distribution of maternal mRNAs during oogenesis and egg activation. Maternal mRNAs begin to be synthesized during the primary growth phase (stages IA and IB). By stages II and III, some mRNAs become localized to the animal pole (green), some mRNAs to the vegetal pole (pink), at least one mRNA (for the gene *vasa*) to the cortex surrounding the entire oocyte (blue), and some mRNAs remain evenly distributed in the oocyte (yellow). This distribution is maintained during egg maturation and ovulation. During egg activation, ooplasmic streaming along axial streamers (orange region, yellow and orange arrows indicate the direction of movement), results in the separation of ooplasm from yolk granules and the formation of the blastodisc. At this time, the various mRNAs are also redistributed. Vegetally localized and uniformly distributed mRNAs are translocated to the forming blastodisc by means of axial streamers (pink and yellow arrows, respectively). The cortically localized *vasa* mRNA becomes enriched in the cytokinetic ring at the boundary between the blastodisc and the yolk cell, possibly through movements along the plane of the cortex (blue arrows). mRNAs localized to the animal pole during oogenesis remain in this same region after egg activation and become distributed in the blastodisc. The location of the micropyle, an actin-based channel at the animal pole of the oocyte that allows the sperm to enter the egg, is indicated. See text for details.

During the following stage, the follicle stage of the primary growth phase (stage IB; follicle diameter 20–140 μm), chromosomes decondense and acquire a lampbrush appearance, where the DNA is highly extended, containing lateral loops with a characteristic morphology, which contain RNA and protein (Baumeister, 1973). This chromosomal configuration is thought to facilitate active transcription of maternal genes, and its appearance coincides with high rates of RNA synthesis in zebrafish oocytes (Baumeister, 1973).

During this stage, both the oocyte and the follicle cells begin to extend microvilli to reach each other. Once formed, these connections contain adherens junctions, desmosomes, and gap junctions, which are likely involved in follicle cell–oocyte communication and the uptake of small molecules by the oocyte (Kessel et al., 1985; Cerdá et al., 1993, 1999). At the same time, components of the vitelline membrane begin to accumulate between the follicle cells and the oocyte, primarily but not exclusively by deposition of oocyte-derived components (Yamagani et al., 1992).

Other structures, like mitochondria, Golgi, and endoplasmic reticulum become abundant, reflecting the requirement to produce large amounts of products. In addition, the Balbiani's vitelline body, also known as the yolk body, forms adjacent to the nuclear envelope. It consists of a heterogeneous complex of mitochondria, annulate lamellae, Golgi bodies, endoplasmic reticulum, and electron-dense fibrogranular material (generally called “nuage;” Clérot, 1976; Kessel et al., 1984), which may be important for trafficking of germ line determinants and other localized RNA and protein products within the oocyte (see below).

The next stages are characterized by the accumulation of massive amounts of protein and lipid important for egg activation and embryogenesis. The cortical alveolus stage (stage II; follicle diameter 140–340 μm) is marked by the appearance of vesicles containing proteins and carbohydrates, presumably produced by the oocyte itself. These structures, called cortical alveoli, gradually accumulate at the oocyte cortex and will eventually be released by exocytosis upon egg activation (Becker and Hart, 1996, 1999), thus modifying the properties of the egg and the vitelline membrane. During the vitellogenesis stage (stage III; follicle diameter, 340–690 μm), yolk precursor protein and lipids accumulate in the oocyte. A primary component of yolk protein, vitellogenin, is exogenously produced by the liver, acquired by the oocyte through endocytosis, proteolytically cleaved, and stored in the oocyte (Wallace, 1985), where it will become a supply of nutrients essential for the developing embryo.

Oocyte growth (and presumably expression of maternal genes and product uptake by the oocyte) ends during the final stage of oocyte maturation (stage IV; follicle diameter 690–730 μm), which is characterized by the migration of the oocyte nucleus, or germinal vesicle, toward the animal pole, the eventual breakdown of the nuclear membrane, and the arrest of meiosis at the second meiotic metaphase. The final stage of ovulation (stage V) involves the release of the oocyte into the lumen of the ovary and is thought to depend on appropriate hormonal stimulation triggered by mating.

mRNA AND PROTEIN DISTRIBUTION DURING OOGENESIS AND THE ANIMAL–VEGETAL AXIS OF THE OOCYTE

As oogenesis proceeds, the animal–vegetal axis of polarity is established in the growing oocyte. Its first morphologic manifestation is the migration of the germinal vesicle from the center of the oocyte toward the prospective animal pole during oocyte maturation, as well as the appearance of a specialized set of cells at the animal pole involved in the formation of the micropylar canal. However, as described below, the analysis of maternal products during oogenesis has shown that the animal–vegetal axis is established much earlier during oocyte formation.

Patterns of mRNA Localization During Oogenesis

Maternal mRNAs fall into four classes according to their localization pattern during oogenesis (Maegawa et al., 1999; Howley and Ho, 2000; Suzuki et al., 2000; Fig. 1):

1
Some mRNAs (Fig. 1, green), such as those for the genes cth1, cyclin-B, notch, PABP, pou-2, taram-A, and zorba, are uniformly distributed in the oocyte during stage I but become localized to the animal pole during stages II and III (Bally-Cuif et al., 1998; Howley and Ho, 2000). Transcripts from the gene Vg1 become concentrated to the same animal region but at a somewhat later stage, during stage IV (Bally-Cuif et al., 1998). In the case of the zorba mRNA, treatment of developing oocytes with microtubule- and microfilament-inhibiting drugs has suggested that, somewhat surprisingly considering studies in other species (Bashirullah et al., 1998), its localization to the animal pole during stage III of oogenesis is independent of both microtubule and microfilament networks (Bally-Cuif et al., 1998). However, these studies do suggest a role for microfilaments in anchoring zorba mRNA at the animal cortex, which is similar to the role of this cytoskeletal network in other systems.
2
mRNAs in a second class of genes (Fig. 1, pink), such as deleted in azoospermia (daz1) and bruno-like, become localized to the vegetal pole of the oocyte at stages IB and II of oogenesis, respectively (Maegawa et al., 1999; Suzuki et al., 2000). Treatments with inhibitors of the cytoskeletal networks indicate that, as with mRNAs localized to the animal pole, anchoring of bruno-like mRNA during oogenesis is dependent on the integrity of the subcortical actin network but apparently independent of microtubules (Suzuki et al., 2000). Upon egg activation, both mRNAs translocate to the animal pole through the process of ooplasmic streaming (Maegawa et al., 1999; Suzuki et al., 2000; see below).
3
Transcripts from a third class of genes (Fig. 1, yellow), which includes activin receptor type II, β-catenin, cdc25, goosecoid, p62, snail, sox19, stat3, and ryk, remain evenly distributed in the egg during oogenesis (Bally-Cuif et al., 1998; Howley and Ho, 2000). Upon egg activation, these mRNAs are transported to the forming blastodisc at the animal pole through the process of ooplasmic streaming (see below).
4
Fourth, the mRNA for the gene vasa, which has been shown to form part of the zebrafish germ plasm, is found throughout the cytoplasm of stage I oocytes and becomes localized at stage II to the cortical region of the entire oocyte (Braat et al., 1999; Howley and Ho, 2000; Knaut et al., 2000; Fig. 1, blue). Upon egg activation, this mRNA is translocated toward the animal pole, possibly along the plane of the cortex (see below).

Protein Expression and Localization During Oogenesis

A thorough study of the distribution of maternal proteins has not been performed, although these would be expected to fall into categories similar to those observed for mRNA localization patterns. In several reported cases, the protein expression patterns consist of specific subcellular distributions, which are consistent with specific functions during oogenesis. The Zorba protein, for example, becomes localized to the animal pole during stage III, where it overlaps with a microtubule-rich region and remains localized until stage IV (Bally-Cuif et al., 1998). This expression pattern is consistent with the localization of zorba mRNA at the animal pole (Bally-Cuif et al., 1998; Howley and Ho, 2000). The Zorba protein contains an RNA recognition motif and its Drosophila homologue is involved in the determination of the polarity of the oocyte (Lantz et al., 1992, 1994; Christerson and McKearin, 1994), possibly by transporting or anchoring of mRNAs. The localized pattern of Zorba protein in zebrafish oocytes suggests that it may have a similar role in zebrafish oogenesis. During egg maturation or fertilization, Zorba protein appears to be rapidly degraded (Bally-Cuif et al., 1998), possibly reflecting that its function in oogenesis has been accomplished and its product is no longer needed in the oocyte and early embryo.

Similarly, catenins and cadherins are localized to cell adhesion junctions between the oocyte and its surrounding follicle cells, and this localization is dissolved during oocyte maturation when the oocyte becomes ready for its release during ovulation (Cerdá et al., 1999). However, in this case, catenins and cadherins are not degraded but are instead stored either as protein complexes (α- and β-catenin complexes), or as free protein (plakoglobin), allowing for their reuse later during embryogenesis. Another example of a protein that is subcellularly localized during oogenesis is the Vasa protein, which is localized in patches on the outer nuclear membrane (Braat et al., 2000; Knaut et al., 2000), where it may have a role in germ line development. After egg maturation, the Vasa protein becomes delocalized (see below).

REDISTRIBUTION OF MATERNAL PRODUCTS DURING EGG ACTIVATION

The events that occur during egg activation and fertilization constitute the transition between oogenesis and embryogenesis. Here, I will restrict this discussion to the redistribution of maternal factors that occurs at this stage. The reader is directed to other articles for a description of other processes associated with this transition, such as fertilization and changes in the micropylar canal (Hart and Donovan, 1983; Hart et al., 1992), exocytosis of cortical alveoli (Becker and Hart, 1996, 1999), vitelline membrane remodeling (Yamagani et al., 1992), and the resumption of meiosis (Streisinger et al., 1981; Selman et al., 1993).

Mature, inactivate zebrafish oocytes contain ooplasm that is intermingled with nonmembrane bound yolk (Roosen-Runge, 1938; Beams et al., 1985). Egg activation occurs upon contact of water and results in the redistribution of ooplasm toward the animal pole to form the blastodisc. Most of the ooplasm appears to move along distinct yolk-free channels, called “streamers,” which connect inner regions of the egg with the base of the blastodisc (Fig. 1). Movement along streamers occurs during the first cell cycle and during interphase in subsequent cycles, up to the sixth cycle (Hisaoka and Firlit, 1960; Beams et al., 1985). Ooplasmic streaming has been proposed to involve two different processes (Leung et al., 1998): a poorly understood “state-change” in the ooplasm/yolk agglomerate that leads to the coalescence of the yolk and the formation of yolk-free streamers, and the generation of force in the ooplasm so that it flows animally along the newly formed streamers.

The force generation process appears to involve the propagation of a slow calcium (Ca⁺⁺) wave from the animal pole to the constriction band at the base of the blastodisc (also termed the cytokinetic ring), and the presence of this wave correlates with the periods of ooplasmic streaming (Leung et al., 1998). This Ca⁺⁺ wave is likely released from the extensive cortical ER network present in the egg (Hart and Fluck, 1995; Leung et al., 1998) and may promote the local contraction of the microfilament network, which itself has been shown to accumulate at this stage at the constriction band (Leung et al., 2000). The contraction of the cortex at the constriction band is thought to result in the flow of ooplasm through the path of least resistance offered by the forming streamers. Ooplasmic streaming (as well as the formation of streamers) is inhibited when eggs are exposed to either Ca⁺⁺ chelators (Leung et al., 1998) or inhibitors of the microfilament, but not the microtubule network (Katow, 1983; Hart and Fluck, 1995; Leung et al., 2000). In the loach Misgurnus fossilis, a teleost with an egg morphology similar to that of the zebrafish, microinjection of microfilament inhibitors reduces ooplasmic streaming when the inhibitor is injected at the animal pole but not when injected at the vegetal pole (Ivanenkov et al., 1987). The cytoskeletal requirements for ooplasmic streaming in zebrafish oocytes thus appear to differ from those observed in other organisms, including medaka fish (Abraham et al., 1993, 1995; Webb et al., 1995), amphibians (Houlinston and Elinson, 1991), and Drosophila (Gutzeit and Koppa, 1982; Therkauf et al., 1992), where ooplasmic streaming is dependent on the function of microtubules. An antibody against heavy myosin chain has been shown to colocalize with cortical actin in zebrafish oocytes (Hart and Fluck, 1995), suggesting that this local contraction may involve myosin as well as actin. Thus, a local Ca⁺⁺- and microfilament-dependent contraction at the animal pole may be producing the force to segregate the ooplasm toward the blastodisc.

In medaka, it has been shown that, although most particles and inclusions move at the same speed and with the same direction as the bulk of the ooplasmic flow, some small inclusions move more rapidly and in a saltatory manner that is dependent on microtubules (Abraham et al., 1993; Webb et al., 1995). In the zebrafish activated egg, injected polystyrene beads move toward the animal pole in a microtubule-dependent, saltatory manner (Jesuthasan and Strähle, 1996; see below). Moreover, the mRNA for the gene squint, which is initially uniformly distributed throughout the egg, segregates during egg activation toward the animal pole through a microtubule-dependent, microfilament-independent process (Gore and Sampath, 2002). These observations suggest that a microtubule network can move ooplasmic components independently of the microfilament-dependent bulk ooplasmic flow. Indeed, ultrastructural analysis suggests the presence of both microfilaments and microtubules in axial streamers (Beams et al., 1985), and an array of parallel microtubules has been found in the oocyte cortex (Jesuthasan and Strähle, 1996). Thus, activated zebrafish eggs use both microfilament and microtubule-based transport systems to redistribute ooplasmic components.

GENETIC NOMENCLATURE

A gene function is referred to as being strictly maternal or strictly zygotic when its corresponding mutant phenotype depends solely on the genotype of, respectively, the female germ line or the embryo. In some cases, zygotic mutations can be tested for maternal effects by determining whether additionally mutating the female germ line increases the strength of the zygotic phenotype. In cases where zygotically mutant embryos are not viable, the creation of a mutant germ line is accomplished by either rescuing the zygotic mutant phenotype through specific treatments (such as the injection of wild-type mRNA for the affected gene; see for example, Gritsman et al., 1999) or creating by cell transplantation chimeric fish carrying a mutant germ line (Ciruna et al., 2002; Waskiewicz et al., 2002). Any observed maternal–zygotic effect presumably reflects functional redundancy between maternal and zygotic products. A particular type of maternal–zygotic effect occurs when a phenotype is caused by heterozygosity, in an otherwise recessive gene, in both maternal and zygotic genetic contributions. Such an effect, referred to as a dominant maternal–zygotic interaction, presumably reflects a sensitivity of the gene function to both maternal and zygotic gene dosages.

GENERAL CELLULAR REQUIREMENTS DURING CLEAVAGE AND GASTRULATION

Early studies showed that a spontaneous, recessive and strictly maternal mutation in the gene janus results in the separation of the blastoderm during the first three cellular divisions, such that two groups of blastomeres form in these embryos (Abdelilah et al., 1994). These first three cellular divisions appear to be specialized. For example, their furrows during cytokinesis are associated with slow waves of intracellular calcium (Chang and Meng, 1995; Webb et al., 1997; Créton et al., 1998). Thus, the janus mutation may affect a process specific for these early cell divisions. Alternatively, the mutation in janus may have a general effect on cytokinesis, but the larger furrows of the early divisions may be more sensitive to an overall reduction in gene function.

More recently, several efforts have carried out screens for recessive maternal-effect mutations using ploidy manipulation methods (Pelegri and Schulte-Merker, 1999; our unpublished data) and family inbreeding strategies (Mullins et al., personal communication). Such screens have and are generating maternal-effect mutations in early cellular processes, including egg polarity and activation, pronuclear fusion, determination of early cellular divisions, DNA segregation during early mitosis, completion of cytokinesis, and cell adhesion.

The recessive maternal-effect mutation in the gene futile cycle (fue) results in defects in nuclear fusion and spindle assembly (Dekens et al., 2003). The regular cleavage pattern shown by anucleate cells in fue mutant embryos (Dekens et al., 2003; Fig. 2), which can be phenocopied by drugs that inhibit DNA synthesis (Knaut et al., 2000), reveals the striking finding that the embryo has a cellular division program that is independent of nuclear material.

Another described recessive maternal-effect mutation, in the gene nebel, affects both membrane deposition at the forming furrows and cell adhesion between daughter cells, as well as the segregation of the germ plasm (Pelegri et al., 1999). This mutation specifically affects the formation of the furrow microtubule array (FMA), a network of microtubules, parallel to each other and perpendicular to the cleavage plane that forms along the length of the furrow (Danilchik et al., 1998; Jesuthasan, 1998). Aside from its role in germ plasm aggregation (see below), the FMA has been implicated in the secretion of intraembryonic membrane vesicles during furrow maturation. These vesicles provide new membrane material needed at cleavage planes and contain cell adhesion molecules, thus explaining the membrane deposition and cell adhesion defects observed in nebel mutant embryos.

Other maternal mutations affect cellular functions required for morphogenesis during gastrulation. Mutations in half-baked exhibit dominant maternal–zygotic interactions that result in defects in epibolic movements that are similar to those observed in zygotically mutant homozygotes (Kane et al., 1996). Mutations in the gene yobo, identified by their zygotic effect on xanthophore pigmentation in larvae, also have a maternal effect on morphogenesis that is independent of the zygotic genotype (Odenthal et al., 1996). Embryos from homozygous yobo mutant mothers develop more slowly and exhibit shortened, broader dorsal axes, which eventually result in head and tail truncations.

In addition, molecular studies have identified factors that are expressed maternally in the early embryo, some of which are discussed below in the context of cell differentiation pathways. One striking example of maternal inheritance is the expression of the gene per3 in oocytes and embryos (Delaunay et al., 2000). The expression of this gene during oogenesis is reflected in the egg such that, regardless of the time of fertilization, the resulting embryo has levels of per3 mRNA that maintain the same synchronicity as the circadian rhythm of the mother.

GERM PLASM IN ZEBRAFISH OOCYTES AND EMBRYOS

Germ plasm, often referred to as nuage, can be observed in many animals as a specialized electron-dense material found in association with other subcellular structures, such as fibrils, mitochondria, and the nuclear membrane, which contains specific mRNAs and proteins and confers the germ cell fate (reviewed in Wylie, 2000). This material has also been observed in the zebrafish, specifically in the developing oocyte and in primordial germ cells (PGCs) during the embryonic stages (Selman et al., 1993; Braat et al., 1999; Knaut et al., 2000).

Two genes, vasa and nanos1, encode mRNA products that localize to the zebrafish germ plasm. Products from both of these genes have been shown to be components of the germ plasm in other species and to have a role in germ cell development. The gene vasa encodes a member of the DEAD box protein family of RNA helicases, which is required for PGC formation in Drosophila (Hay et al., 1988; Lasko and Ashburner, 1988; Liang et al., 1994) and C. elegans (Gruidl et al., 1996), and has been suggested to have a role in the translational regulation of PGC-specific transcripts. The gene nanos, which encodes an RNA binding zinc finger protein (Wang and Lehmann, 1991), is also required for proper development of the PGCs in Drosophila (Kobayashi et al., 1996; Forbes and Lehmann, 1998; Deshpande et al., 1999) and C. elegans (Subramaniam and Seydoux, 1999). In zebrafish, a role for vasa and nanos1 function in PGC specification has not been demonstrated, although morpholino-mediated reduction of nanos1 function results in defects in PGC migration and survival during embryogenesis (Köprunner et al., 2001). However, the mRNA products for these genes act as specific markers for the germ plasm, which allows one to easily follow its distribution.

Segregation of mRNAs Present in the Germ Plasm

The mRNA for the gene vasa has been shown to exhibit an elaborate and precise pattern of localization (Fig. 3). Remarkably, many general features of this process are very similar to the segregation of germ plasm in Xenopus (Ressom and Dixon, 1988). As mentioned above, vasa mRNA, although initially found throughout the cytoplasm, becomes localized to the cortex of stage II oocytes, where it remains until egg activation (Braat et al., 1999; Howley and Ho, 2000; Knaut et al., 2000). Of interest, the localization of the vasa mRNA to the cortex during oogenesis roughly coincides with the development of the Balbiani's yolk body. This structure has been suggested to be analogous to the mitochondrial cloud in Xenopus, which is involved in the segregation of mRNA and protein products, including germ plasm components, to the vegetal cortex (King et al., 1999). Thus, it will be important to determine the precise relationship between vasa mRNA and other germ plasm components and the Balbiani's yolk body.

At the one-cell stage, vasa mRNA becomes transiently localized to the constriction band at the base of the forming blastodisc (Braat et al., 1999). At this stage, vasa mRNA is not observed in axial ooplasmic streamers, indicating that it may instead accumulate at the cortical band by moving along the plane of the cortex. As the first and second cleavage furrows form, vasa mRNA is recruited to the furrow, initially as a rod-shaped structure that spans more than half of the distal region of the furrow (Yoon et al., 1997; Pelegri et al., 1999). During this time, f-actin aggregates at the furrow to form the actomyosin ring required for cytokinesis (Dekens et al., 2003). Thus, it is possible that vasa mRNA recruitment to the furrow is dependent on underlying movements of f-actin. This conclusion is consistent with ultrastructural analysis, which shows a tight colocalization of vasa mRNA and the actin cortex at the one-cell stage embryo (Knaut et al., 2000).

During furrow maturation, the vasa mRNA-containing germ plasm coalesces into a tight aggregate at the distal ends of the furrow (Yoon et al., 1997; Pelegri et al., 1999). Colocalization studies show that the tubules of the FMA, which as the furrow matures also accumulate in the same region of the furrow (Danichick et al., 1998; Jesuthasan, 1998), are embedded in this aggregate (Pelegri et al., 1999; Knaut et al., 2000). nebel mutant embryos, which have defects in FMA formation, exhibit defects in the peripheral aggregation of vasa mRNA and ultrastructurally defined germ plasm, and treatment with microtubule inhibiting drugs during furrow maturation phenocopies this defect (Pelegri et al., 1999; our unpublished data). These observations suggest that germ plasm aggregation depends on the movement of FMA tubules toward the peripheral end of the furrow.

The processes of recruitment and aggregation occur at the furrows of the first and second cellular cleavages, resulting in four aggregates, one at each of the two ends of the furrows. Recruitment and aggregation of smaller vasa mRNA-containing aggregates can be occasionally observed during the third cleavage, suggesting that vasa mRNA remaining in the cortex continues to follow the same subcellular recruitment and aggregation program. However, these smaller aggregates are not maintained, possibly due to a lack of a critical mass of germ plasm, and are removed through a process of active degradation (Wolke et al., 2002; see below).

At the 32-cell stage, these four germ plasm aggregates ingress into four cells, where they remain subcellularly localized (Yoon et al., 1997; Braat et al., 1999). Between the 32-cell stage and the sphere stage (cell cycle 13), these aggregates segregate asymmetrically during cell division, so that only four descendant cells inherit the germ plasm (Yoon et al., 1997; Braat et al., 1999; Knaut et al., 2000). In each of these cells, a subcellularly localized vasa mRNA-containing aggregate forms a cup-shaped structure that is often in apparent association with one of the spindle poles (Braat et al., 1999; Knaut et al., 2000). This program of asymmetric segregation changes at the sphere stage, when vasa mRNA becomes evenly distributed in the cell and is inherited during cell division by both daughter cells, a pattern that will be maintained during the remainder of embryogenesis (Yoon et al., 1997; Braat et al., 1999; Knaut et al., 2000). Unexpectedly, the transition between the early asymmetric segregation and the later symmetric segregation occurs in embryos where DNA replication or transcription have been inhibited by exposure to drugs (Knaut et al., 2000). This indicates that this change in localization pattern does not depend on either the nucleocytoplasmic ratio or the initiation of zygotic transcription at the MBT but depends instead on an unknown counting mechanism of maternal origin.

The localization of vasa mRNA to the germ plasm has been shown to depend on its 3′ untranslated (UTR) region. The 3′UTR region of the vasa mRNA can confer furrow localization to reporter mRNAs in transgenic zebrafish expressing those constructs during oogenesis (Knaut et al., 2002). This region is also capable of conferring localization of a reporter mRNA to the vegetal pole of Xenopus embryos, demonstrating conservation in the mechanism of mRNA localization in these species. In both cases, the region required for the localization could be narrowed down to the same 180-nucleotide region within the 3′UTR region.

Recently, the nanos1 mRNA has been reported to localize to the first and second cleavage furrows in a pattern identical to that of vasa mRNA localization (Köprunner et al., 2001). This finding suggests that, during early development, vasa mRNA, nanos1 mRNA, and other maternal products segregate together as a multicomponent germ plasm aggregate. The precise localization pattern of this aggregate likely reflects the importance of its function in the early distinction of germ cells from somatic cells.

Regulation of Expression of Germ Plasm Products

Further studies have indicated the presence of additional levels of regulation of the germ plasm-associated mRNAs vasa and nanos1 and their products, specifically at the level of mRNA stability (Köprunner et al., 2001; Wolke et al., 2002) and translatability (Köprunner et al., 2001) and at the level of protein stability (Wolke et al., 2002). In all of these cases, the regulation of these products results in their enrichment in PGCs and interferes with their accumulation in somatic cells, in a manner reminiscent of the localization and translational regulation of germ plasm components in Drosophila (Lipshitz and Smibert, 2000).

In addition, the Vasa protein localizes to perinuclear patches around the germinal vesicle both during oogenesis and during embryogenesis beginning at the sphere stage (cell cycle 13; Knaut et al., 2000; Wolke et al., 2002). However, these patches are distinct from the vasa mRNA-containing, structurally defined germ plasm (Knaut et al., 2000). Moreover, in embryos at the early cleavage stages, Vasa protein does not localize to the sites of germ plasm aggregation (Braat et al., 2000; Knaut et al., 2000). Thus, Vasa protein is not a component of the germ plasm, and, although its subcellular localization suggests a role for this product in germ cell development, its relation to germ plasm function remains unclear.

Of interest, Vasa protein levels in PGCs increase after the activation of zygotic vasa gene expression at the late sphere stage (cell cycle 13; Knaut et al., 2000), and normal levels of Vasa protein accumulation are dependent on the presence of a nucleus (Knaut et al., 2000). These observations suggest that the accumulation of Vasa protein in PGCs is largely a result of translation from zygotically derived vasa mRNA transcripts. However, in the absence of a nucleus, Vasa protein does accumulate, albeit at reduced levels, in cells containing maternally derived vasa mRNA (Knaut et al., 2000). Thus, maternally localized vasa mRNA may be able to promote an initial enrichment of Vasa protein in PGCs. Maternally derived Vasa protein could in turn initiate, possibly by the translational activation of specific transcripts, a cascade of events, including zygotic vasa gene expression, leading to a PGC-specific developmental program.

MATERNAL FACTORS INVOLVED IN DORSOVENTRAL PATTERNING

Three major signaling pathways have been implicated in the establishment of dorsoventral polarity in the early zebrafish embryo: Wnt/β-catenin, Wnt/calcium, and Bmp signaling (Fig. 4).

Determination of an Axis-Induction Center by Wnt/β-Catenin Signaling

Removal of the vegetal-most yolk during the early cell cycles in a variety of teleosts, including the zebrafish, results in radially symmetric embryos that lack axial structures (Oppenheimer, 1936; Tung et al., 1945; Mizuno et al., 1999; Ober and Schulte-Merker, 1999), indicating that this region contains a factor necessary for dorsal axis determination. The same manipulation at later stages causes progressively weaker effects, such that, for example, in zebrafish, by the eight-cell stage the majority of the operated embryos do not show axial defects. At the midblastula stages, the region of the yolk cell normally underlying the blastoderm, when isolated and juxtaposed to blastoderm cells of a different embryo, can induce dorsal mesoderm genes (as well as general mesodermal genes) in these cells (Mizuno et al., 1996). This dorsal-inducing activity is not present in isolated yolk cells derived from embryos where the vegetal yolk had been removed at early stages (Mizuno et al., 1999). Together, these experiments show the presence of a factor essential for dorsal axis induction, which is localized at the vegetal cortex in the freshly laid egg and which, during the early cleavage stages, moves animally to a region of the yolk cell underlying the cellular blastoderm.

The animally oriented movement of the dorsal determinant appears to depend on the microtubule network (Jesuthasan and Strähle, 1996). Treatments that inhibit microtubule polymerization, when carried out transiently during the first 15 min after fertilization, result in defects in axis induction. Moreover, injection of fluorescent beads at the vegetal pole reveals a microtubule-dependent saltatory movement of particles along a cortical path and toward the blastoderm cells at the animal pole, which mimics the movement of the endogenous dorsal determinant. Approximately at this same stage, a parallel array of microtubules forms at one side of the vegetal pole, presumed to be the prospective dorsal side. Thus, current evidence indicates that the vegetally localized dorsal signal moves animally during the early cell cycles along cortical microtubule-based tracts. A role for the microfilament network in transport or anchoring of the dorsal signal has not been demonstrated, although overexpression and functional knockdown analysis of the actin filament severing factor gelsolin, which is provided maternally in the embryo, suggests a role for this factor in dorsal axis induction (Kanungo et al., 2003).

The initial vegetal localization and subsequent cortical translocation of a dorsal determinant during early stages in teleosts is remarkably similar to the situation in amphibians. However, in amphibians, the microtubule-dependent movement of the dorsal determinant is coupled to cortical rotation, a general rotation of the egg cortex with respect to its inner core (Gerhart et al., 1989). Zebrafish embryos, on the other hand, do not have a detectable cortical rotation (Ho, 1992) and may rely instead on a more restricted transport system. However, the similarities between the two systems suggest that they may have a common underlying mechanism.

The translocated dorsal signal results in the local activation of the canonical Wnt signaling pathway, also referred to as the Wnt/β-catenin pathway (reviewed in Wodarz and Nusse, 1998; Huelsken and Birchmeier, 2001). Wnt/β-catenin signaling is activated by a subclass of secreted ligands of the Wnt family by binding to seven-transmembrane receptors of the Frizzled (Fz) family and coreceptors of the low-density lipoprotein receptor-related protein (LRP) family. The activated receptor complex signals intracellularly by means of the protein Dishevelled (Dsh), which in turn regulates the activity of a multiprotein complex, composed of casein kinase I (CKI), Axin, the adenomatous polyposis tumor suppressor protein (APC), Diversin, and glycogen synthase kinase (GSK-3), which normally targets cytoplasmic β-catenin (βcat) for degradation (reviewed in Polakis, 2000; see also Schwarz-Romond et al., 2002). Local activation of Wnt/βcat signaling results in the stabilization of the cytoplasmic pool of βcat protein. Stabilized βcat protein enters the nucleus, where it interacts with members of the Tcf/Lef family of HMG-box transcription factors to regulate transcriptional activity of target genes (reviewed in Eastman and Grosschedl, 1999; Sharpe et al., 2001). Manipulation of Wnt/βcat signaling by using mRNA injection or morpholino-mediated knockdowns in early zebrafish embryos supports a role for this pathway in dorsal axis induction. Treatments expected to increase Wnt/βcat signaling result in the expansion of dorsal cell fates (Kelly et al, 1995a, b, 2000; Nasevicius et al., 1998; Sumoy et al., 1999; Heisenberg et al., 2001), whereas treatments expected to reduce Wnt/βcat signaling inhibit dorsal induction (Nasevicius et al., 1998; Pelegri and Maischein, 1998).

Exactly how the Wnt/βcat pathway becomes activated in the early embryo remains controversial. Several studies in Xenopus embryos showed that overexpression of products that interfere with the Wnt/βcat pathway at a level at or upstream of Dsh do not affect the induction of the dorsal axis (Hoppler et al., 1996; Sokol, 1996; Leyns et al., 1997), suggesting that the activation of the Wnt/βcat pathway may be initiated by an intracellular factor. In Xenopus-activated eggs, Dsh protein associates with vesicle-like structures that translocate toward dorsal regions in a manner dependent on microtubules and the cortical rotation (Miller et al., 1999), thus closely mirroring the properties expected of the dorsal signal. In addition, studies in Xenopus have shown that activation of Wnt/βcat signaling results in the phosphorylation of Dsh (Yanagawa et al., 1995; Semenov and Snyder, 1997), and that Dsh protein is preferentially phosphorylated in the dorsal side of the embryo at the time when dorsal induction is established (Rothbächer et al., 2000). Dsh has been shown to interact with a diverse set of proteins (reviewed in Wharton, 2003), which could be involved in its transport or regulation. Another potential site for the intracellular activation of Wnt/βcat signaling is at the level of GSK-3. In particular, studies in Xenopus (Yost et al., 1998) and zebrafish (Sumoy et al., 1999) have shown that the GSK-3 binding protein (GBP) is maternally expressed, results in the stabilization of βcat, and induces ectopic axes when overexpressed, and, at least in Xenopus, is required for axis induction.

However, recent studies have shown that the reduction in Frizzled receptor function results in the production of axial defects both in zebrafish (Nasevicius et al., 1998) and in Xenopus (Sumanas et al., 2000), raising the question of whether reception of a Wnt ligand is required for axis determination. In zebrafish, both wnt8 and fzA mRNAs are provided maternally and continue to be expressed in the dorsal marginal region after the onset of zygotic transcription (Kelly et al., 1995b; Nasevicius et al., 1998), which is consistent with an early role of these genes in axis induction. One model that could incorporate these data is that dorsal induction is initiated intracellularly, possibly by translocation or modification of Dsh or GSK-3, and that this initial asymmetry is subsequently amplified by a positive feedback loop dependent on Wnt8 and FzA. More research will be necessary to resolve this uncertainty.

In zebrafish embryos, βcat protein can be observed to accumulate in the nuclei of the dorsal yolk syncytial layer (YSL) and dorsal marginal blastomeres at the midblastula stages (Schneider et al., 1996). The YSL layer consists of an acellular nuclear layer directly underlying the blastoderm, which begins to form at the tenth mitosis by regression of the membranes of the marginal most cells and nuclear division in the absence of cytokinesis (Kimmel et al., 1995). The marginal blastomeres themselves remain connected to the yolk cell throughout the early cleavages. Thus, maternal factors such as the presumptive dorsal signal can be acquired by the YSL either from marginal blastomeres or directly from the yolk cell.

A recessive, maternal-effect mutation in the gene ichabod produces embryos with severe axis-induction defects similar to those produced by embryologic manipulations that delete the dorsal signal (Kelly et al., 2000). Mutant embryos exhibit reduced levels of βcat protein localized to the nucleus, further implicating βcat nuclear accumulation as an essential step in axis induction. Of interest, the axis-induction defect in ichabod embryos cannot be rescued by mRNAs coding for components in the Wnt/βcat signaling pathway expected to increase the stability of βcat protein. Thus, ichabod function appears to be important in an unknown step in βcat nuclear localization that is independent of βcat protein stabilization.

The effects of βcat nuclear accumulation, originally attributed to transcriptional activation by the βcat/Tcf complex (Clevers and van de Wetering, 1997), have also been shown to be mediated by the regulation of Tcf-dependent transcriptional repression upon βcat binding (reviewed in Eastman and Grosschedl, 1999; Sharpe et al., 2001). In Xenopus embryos, in the absence of βcat, Tcf factors bind target genes and lead to their transcriptional repression (Brannon et al., 1997), and depletion of maternally provided XTcf-3 results in ectopic expression of dorsal genes during gastrulation (Houston et al., 2002). These data suggest that, at least in amphibians, the primary role of βcat protein in early embryos is to relieve Tcf-3–mediated repression of dorsal genes in the organizer region.

It is not yet clear whether this is also the case in the early zebrafish embryo, which contains maternal mRNA for two tcf-3 homologs, tcf-3 (also called headless) (hdl) (Pelegri and Maischein, 1998; Dorsky et al., 1999; Kim et al., 2000), and tcf-3b (Dorsky et al., 1999), as well as for lef-1 (Dorsky et al., 1999). Expression of dominant-negative constructs containing the DNA binding domain of Tcf-3 but lacking its βcat-interacting domain result in the reduction of dorsal-specific gene expression (Pelegri and Maischein, 1998). However, Tcf and Lef proteins bind to similar regulatory DNA elements (Waterman et al., 1991), so it is unclear which specific Tcf/Lef factor is normally involved in axis determination. Interestingly, the presence of maternal lef-1 mRNA in zebrafish eggs (Dorsky et al., 1999) contrasts with the situation in Xenopus, where this gene is expressed only zygotically (Molenaar et al., 1996; see also Roël et al., 2002) and may be indicative of a different mode of early dorsal gene regulation in these organisms. Dorsal-specific expression is largely normal in several circumstances affecting Tcf/Lef factors, such as the elimination by mutation of both maternal and zygotic Tcf-3/Hdl product (Kim et al., 2000), the simultaneous morpholino-mediated reduction of both Tcf-3/hdl and Tcf-3b (Dorsky et al., 2003) and the morpholino-mediated reduction of Lef-1 function (Dorsky et al., 2002). On the other hand, the dorsal expression of a reporter transgene containing Tcf/Lef consensus binding sites closely resembles the expression of lef-1 but not that of the tcf-3 genes and is dependent on Lef-1 function but not Tcf-3/Hdl function (Dorsky et al., 2002), which suggests that at least some dorsally expressed genes may also be transcriptionally activated by a βcat/Lef-1 complex. Further analysis will help to resolve these uncertainties.

Expression profiles suggest that Wnt/βcat signaling directly activates zygotic dorsal target genes such as those coding for the transcription factor Bozozok (Boz; also called Dharma and Nieuwkoid; Koos and Ho, 1998; Yamanaka et al., 1998; Fekany et al., 1999), the BMP antagonist Chordin (Chd; Fisher et al., 1997; Schulte-Merker et al., 1997), the Wnt antagonist Dkk1 (Hashimoto et al., 2000; Shinya et al., 2000), and the nodal-related transforming growth factor-beta (TGF-β) signal Squint (Shimizu et al., 2000; Schier and Talbot, 2001). In the case of boz, Tcf/Lef binding sites have been shown to be present in the promoter region and a small promoter fragment containing these sites recapitulates dorsal expression (Ryu et al., 2001). Overexpression and loss-of-function studies support the idea that Wnt/βcat signaling acts directly on these early zygotic targets, which in turn mediate the axis-inducing activity of this pathway (reviewed in Schier, 2001).

Wnt/Calcium Signaling May Down-regulate Dorsal Signals in Early Embryos

The Wnt/calcium signaling pathway is a βcat-independent pathway, which appears to be mediated by calcium (Ca⁺⁺) release (reviewed in Kühl et al., 2000b; Pandur et al., 2002). This noncanonical pathway is thought to be triggered by a subclass of Wnt ligands (e.g., Wnt-4, Wnt-5A, and Wnt-11) different from those that can activate the canonical Wnt/βcat pathway (e.g., Wnt-1 and Wnt-8). These ligands are received by a subclass of Frizzled receptors and transduced by means of G-protein signaling (Slusarski et al., 1997a; Sheldahl et al., 1999), which in turn results in the activation of phospholipase C (PLC) isozymes (Kume et al., 2000). Activated PLC stimulates the phosphatidylinositol (PI) cycle by hydrolyzing phosphatidylinositol 4,5 bisphosphate (PIP₂) to release inositol 1,4,5-trisphosphate (IP₃), which promotes the release of Ca⁺⁺ from the endoplasmic reticulum (reviewed in Berridge, 1993). Another product of PIP₂ hydrolysis is diacylglycerol, which stimulates protein kinase C (Sheldahl et al., 1999).

Both in Xenopus (Torres et al., 1996) and zebrafish (Slusarski et al., 1997b), coexpression of Wnt5 blocks the ability of Wnt8 to activate the Wnt/βcat pathway. A similar suppressive effect can be observed in zebrafish by increasing intracellular Ca⁺⁺ levels by ectopic expression of the serotonin receptor (Slusarski et al., 1997b), indicating that this interaction occurs downstream of Ca⁺⁺ signaling. Thus, Ca⁺⁺ released by Wnt/Ca⁺⁺ signaling appears to negatively regulate Wnt/βcat signaling.

Aperiodic Ca⁺⁺ fluxes have been observed in zebrafish embryos in cells at the blastula stage (Reinhard et al., 1995), and expression of Wnt5 increase the frequency of these fluxes (Slusarski et al., 1997a, b). Both endogenous and ectopic Ca⁺⁺ fluxes are dependent on G-protein and PI signaling (Slusarski et al., 1997a). Inhibition of this pathway at various levels, including PLC activity, PI cycling, and Ca⁺⁺ release, results in the ectopic activation of the Wnt/βcat pathway (Westfall et al., 2003). Similar results in Xenopus support a role for the Wnt/Ca⁺⁺ pathway in the down-regulation of dorsal cell fates induced by Wnt/βcat signaling (Ault et al., 1996; Kume et al., 1997, 2000).

In Xenopus, experiments have indicated that the promotion of ventral cell fates by Wnt/Ca⁺⁺ signaling may be mediated by Ca⁺⁺ sensitive targets such as Ca⁺⁺/calmodulin-dependent protein kinase II (CaMKII; Kühl et al., 2000a) and the serine/threonine phosphatase calcineurin (Saneyoshi et al., 2002). Calcineurin in turn has been shown to activate the factor NF-AT, which negatively regulates the Wnt/βcat pathway at a level downstream of Dsh but upstream of GSK-3 (Saneyoshi et al., 2002). Further work will be needed to test which Ca⁺⁺-sensitive regulatory factors mediate Wnt/Ca⁺⁺ signaling in zebrafish and how they modulate Wnt/βcat signaling.

Ventral Pathway Dependent on Factors of the Bmp Family of TGF-β Ligands

Signaling by members of the TGF-β family of extracellular factors has been shown to have an important role in the induction of ventral cell fates in the embryo. This pathway is typically activated by binding of TGF-β family factors to a dimeric complex of type I and type II receptors, which upon ligand binding phosphorylates and activates Smad proteins, which in turn activate transcription of downstream targets (reviewed in Massague, 1998).

The gene radar, which encodes a TGF-β factor of the Bmp family, is maternally expressed, and its mRNA is uniformly distributed in the embryo (Goutel et al., 2000). Overexpression and morpholino knockdown studies show that radar is involved in the specification of ventral cell fates (Goutel et al., 2000; Sidi et al., 2003). Radar protein promotes ventral cell fates by activating the expression of other Bmp genes, which in the zebrafish are ventrally expressed and which have been shown to have an important role in the specification of early dorsal–ventral axis in vertebrates (reviewed in Hogan, 1996; Mullins, 1998). Molecular analysis has shown that bmp2b and bmp7 correspond to the strictly zygotic genes swirl (Kishimoto et al., 1997; Nguyen et al., 1998) and snailhouse (snh; Dick et al., 2000; Schmid et al., 2000), respectively, which when mutated result in defects in ventral cell fate development. radar function has been shown to be required and sufficient for the expression of bmp2b/swirl and another zygotic Bmp gene, bmp4 but appears to not be essential for the expression of bmp7/snh (Goutel et al., 2000; Sidi et al., 2003). Activation of bmp2b is independent of the translation of zygotic products (Leung et al., 2003), which suggests that it relies directly on a radar-dependent maternal pathway.

Molecular genetic experiments have shown that the Alk8/Lost-a-fin (Laf) TGFβ type I receptor is maternally provided and both maternal and zygotic products are important for its overall function (Bauer et al., 2001; Mintzer et al., 2001). Simultaneous functional reduction of Radar and Alk8/Laf have a synergistic effect on ventral development and the expression of downstream Bmp genes (Sidi et al., 2003), suggesting that Radar may be acting through the Alk8/Laf type I receptor. However, overexpression studies on embryos lacking zygotic Alk8/Laf product has also suggested a role for this factor further downstream in a ventralizing pathway, specifically in the reception of zygotic Bmp signals (Bauer et al., 2001; Mintzer et al., 2001). It is possible, therefore, that Alk8/Laf is used at different stages to receive both Radar and Bmp signals.

Mutations in the intracellular TGF-β signaling factor smad5/somitabun (sbn, also known as captain hook [cpt], and piggytail [pgy]) exhibit dominant maternal-effects and maternal–zygotic interactions that result in dorsalized phenotypes (Mullins et al., 1996; Kramer et al., 2002), thus showing a requirement for the maternal product of this gene in ventral cell specification. Specifically, Smad5/Sbn maternal function appears important in the induction of bmp7 but not bmp2b expression (Kramer et al., 2002), a role that appears to be the reverse of that of radar. Thus, Radar and Smad5/Sbn may form part of independent signaling pathways that, together, result in the coordinated expression of Bmp2b and Bmp7 ligands, which themselves are thought to act as a heterodimer pair (Schmid et al., 2000). However, overexpression and epistasis analysis are also suggestive of a role for Smad5/Sbn as a downstream factor in Bmp2b signaling (Dick et al., 1999; Hild et al., 1999), indicating that maternally provided Smad5/Sbn product, as in the case of Alk8/Laf, may perdure after zygotic gene activation to function downstream of zygotic Bmp genes.

Like the Wnt/βcat target chordin, the gene ogon (also known as mercedes and short tail) normally has a dorsalizing, zygotic function so that homozygous mutants exhibit a partially ventralized phenotype (Hammerschmidt et al., 1996; Solnica-Krezel et al., 1996; Walker, 1999). However, unlike chordin, ogon function also has a maternal genetic contribution (Miller-Bertoglio et al., 1999; Wagner and Mullins, 2002; Fig. 5). Recently, ogon has been reported to encode a secreted Frizzled-related factor (Sizzled [szl]), which has sequence similarity to the Wnt Frizzled receptor and has both ubiquitous maternal expression and zygotic expression in ventral cells (Yabe et al., 2003). Unexpectedly, ogon/szl does not appear to be involved in Wnt signaling in the zebrafish embryo. Instead, maternal and zygotic Ogon/Szl products appear to act as dorsalizing factors by mediating a negative regulatory feedback loop acting on Bmp signaling, presumably to regulate zygotic Bmp activity in ventral regions. These molecular genetic studies indicate that a ventral to dorsal gradient of zygotic Bmp activity, initiated by maternal factors and further refined by zygotically acting genes and, in some cases, perduring maternal factors, helps to define positional values along the dorsoventral axis.

To summarize this section, our current knowledge suggests a model for dorsoventral patterning in the early embryo, which is controlled by a combination of three different processes, all of which are initiated by maternal factors (Fig. 4). Ubiquitous ligands such as Radar appear to promote expression of zygotic Bmp genes throughout the embryo. Activation of the Wnt/βcat pathway in the dorsal side results in the stabilization of βcat and the activation in this region of dorsal target genes such as boz and chordin, which in turn results in the down-regulation of zygotic Bmp gene expression in the dorsal side. In particular, Boz has been shown to directly repress the expression of bmp2b in dorsal regions (Leung et al., 2003). Ca⁺⁺ transients occurring during the cleavage stages, activated by Wnt/Ca⁺⁺ signaling may exert a negative regulatory effect on Wnt/βcat signaling, which may be important in determining the sharpness of the resulting activity gradients and gene expression profiles (Meinhardt and Gierer, 2000). Zygotic Bmp gene expression is stabilized by positive (Bmp-dependent) and negative (Ogon/Szl-dependent) autoregulatory feedback mechanisms, and Bmp signaling helps maintain the boundaries of expression of Bmp antagonists such as Chordin. This cascade of events eventually leads to the localized activation of other target genes and signaling pathways involved in the refinement of dorsoventral patterning (reviewed in Schier, 2001; see also Leung et al., 2003).

ANTERIOR–POSTERIOR AXIS DETERMINATION

In comparison to dorsoventral patterning, few maternal factors have been reported to be involved in anteroposterior patterning in zebrafish embryos. This situation may reflect that the anteroposterior axis is induced at later stages than the dorsoventral axis, and, therefore, may be less dependent on the earlier-acting maternal products. However, this idea remains to be proven, and the observed differences may simply indicate our generally less complete knowledge of this field.

A preexisting anteroposterior pattern has been shown to exist in the zebrafish epiblast by the onset of gastrulation. This pattern is demonstrated by the finding that, when neural cells are ectopically induced at different positions along the animal–vegetal axis of the early gastrula epiblast, which at this stage is roughly aligned with the anteroposterior axis, the induced neural cells express anteroposterior genes according to their position along this axis (Koshida et al., 1998; Nikaido et al., 1999). This phenomenon also occurs in embryos where the dorsoventral pattern is altered by either surgical removal of the vegetal cortex or interference with Bmp function, demonstrating that anteroposterior patterning of the zebrafish epiblast can occur independently of dorsoventral patterning. Additional experiments have shown that transplantation of isolated yolk cells onto host epiblasts can modify the endogenous anteroposterior induction of neural markers in the hosts, suggesting that a signal from the yolk cell, or from marginal mesoderm induced by the yolk cell, is involved in the anteroposterior patterning of the epiblast (Koshida et al., 1998).

Another organizing center that is capable of patterning the embryo along its anteroposterior axis is the anterior-most row of cells in the neural plate. Ablation and transplantation experiments have shown that this row of cells is the source of a secreted anteriorizing signal (Houart et al., 1998). The inducing properties of this row of cells are present before the arrival of the leading edge of the involuting dorsal mesoderm, suggesting that the induction of this organizing center is mediated by the animal-most region of the YSL.

Thus, signals from the YSL are likely candidates to induce organizing centers that pattern the embryo along the anteroposterior axis, although it is not clear whether such signals are of maternal or zygotic origin. It is possible that maternal posteriorizing or anteriorizing signals could be localized to the blastoderm margin or the animal most region of the YSL, respectively. Such maternal signals could be acting directly, or could act indirectly to induce the expression of zygotic factors in the YSL, which themselves would lead to the patterning of the overlying epiblast. Indeed, expression of genes in the YSL appears to be finely patterned, as some genes, such as boz (Koos and Ho, 1998; Yamanaka et al., 1998; Fekany et al., 1999) and squint (Schier and Talbot, 2001) are expressed in the dorsal YSL margin, whereas others such as hex are expressed in the dorsal YSL in a region extending anteriorly to reach the animal pole (Ho et al., 1999). The identity of maternal factors, if any, which would direct such localized zygotic patterns of gene expression, remains unknown.

Detailed analysis of a handful of genes, however, has shown that some maternal products perdure after MBT and are required for anteroposterior brain patterning. Genetic analysis has shown a role of maternally derived Tcf-3/Hdl in the development of anterior brain structures (Kim et al., 2000). Specifically, Tcf-3/Hdl appears to promote the basal repression of genes that direct the formation of posterior regions of the brain, which in turn allows expression of genes that determine anterior brain development.

Another gene with a significant maternal genetic contribution and which affects anteroposterior brain patterning is lazarus(lzr)/pbx4. Removal of the maternal contribution of lzr/pbx4 enhances the zygotic phenotype caused by mutations in this gene and results in defects in hindbrain segmentation and homeotic transformations of rhombomeres r2-r6 to a rhombomere r1 identity (Waskiewicz et al., 2002). For both Tcf-3/Hdl and Lzr/Pbx4, the function of the gene occurs well after the initiation of zygotic transcription at MBT. This further exemplifies that post-MBT processes may be driven not only by newly transcribed, zygotic products, but also, at least for some genes, by perduring maternally derived factors.

MATERNAL REQUIREMENTS FOR GERM LAYER SPECIFICATION

The maternal requirements for germ layer specification remain incompletely understood, although some progress has been done in recent years to understand the induction of the mesendodermal layer. Yolk cell transplantations have shown that, at the blastoderm stage, the yolk cell contains signals that can induce both mesodermal and endodermal genes in the overlying marginal cells (Mizuno et al., 1996; Ober and Schulte-Merker, 1999; Rodaway et al., 1999). These signals appear to be in the form of mRNA, because injection of RNase into the yolk cell at the blastula stage inhibits the expression of ventrolateral mesendodermal genes (but not dorsal mesendodermal gene expression, which appear to be stabilized by a βcat-dependent process that is insensitive to this treatment; Chen and Kimelman, 2000). These signals, however, could consist of either maternal mRNA or newly transcribed zygotic mRNAs. One candidate for such a factor is the mRNA for the nodal-related gene squint, a member of the TGF-β family. This gene is zygotically expressed in the YSL and marginal cells, and, together with another zygotically expressed, nodal-related gene, cyclops, is involved in mesendoderm induction (Feldman et al., 1998).

The identity of the maternal factor(s) involved in the activation of zygotic mesendodermal inducers such as squint in the marginal zone of the embryo is still unknown (although, as discussed above, Wnt/βcat signaling activates squint in the dorsal-most cells). In Xenopus, VegT, a maternal transcription factor whose mRNA is localized to the vegetal egg cortex, has been shown to be required for zygotic expression of nodal-related genes involved in mesendoderm induction (reviewed in Whitman, 2001). However, the zebrafish homolog of VegT is not expressed before squint and cyclops zygotic expression (Ruvinsky et al., 1998), indicating that, in zebrafish, these genes use a different early activator. Activin induces mesoderm and a dominant negative Activin receptor blocks mesoderm induction (Wittbrodt and Rosa, 1994; Ober and Schulte-Merker, 1999), and maternally derived activin βB mRNA has been shown to be present, albeit at low levels, in early embryos (Rodaway et al., 1999). However, a dominant negative Activin cleavage mutant variant that results in the depletion of newly synthesized Activin has no effect on mesoderm induction in medaka (Wittbrodt and Rosa, 1994), suggesting that endogenous Activin is not involved in this process. Instead, the effects of Activin and dominant negative Activin receptors on mesoderm induction can be explained by cross-activation of the nodal signaling pathway, which uses the same set of receptors (Gritsman et al., 1999). Although squint mRNA is supplied maternally, it is not localized to the YSL (Feldman et al., 1998; Gore and Sampath, 2002). Moreover, embryos defective in the reception of nodal signals still exhibit the initial induction of ventrolateral mesoderm (Feldman et al., 1998; Gritsman et al., 1999), indicating that the endogenous inducer is likely not a nodal signal. Thus, further studies are needed to determine the identity of the endogenous mesendodermal signal.

Reception of Squint and Cyclops by the Activin receptor requires the function of the gene one-eyed pinhead (oep), which encodes an EGF-CFC family coreceptor that is provided both maternally and zygotically (Zhang et al., 1998; Gritsman et al., 1999). Embryos mutant for both maternal and zygotic Oep function (MZoep mutants) exhibit defects in mesendoderm induction that are significantly more severe than when only zygotic Oep function is affected (Gritsman et al., 1999), indicating an involvement of maternal Oep product in this process. Strikingly, the MZoep phenotype is identical to that observed in embryos zygotically mutant for both squint and cyclops (Feldman et al., 1998), which is consistent with a role of Oep as a coreceptor for these two nodal-related factors.

A similar maternal–zygotic functional requirement has been demonstrated for the gene schmalspur (sur), which codes for the forkhead transcription factor FoxH1/FAST1 and which associates with Smad2 to effect expression of target genes (Pogoda et al., 2000; Sirotkin et al., 2000). In the case of sur, however, the MZsur phenotype is significantly weaker, affecting only dorsal mesoderm formation, than that observed in MZoep mutants. This finding suggests that sur is not the only target of nodal signaling involved in mesendoderm induction. Thus maternal factors have an important role in the induction of the mesendodermal layer. squint is activated in the dorsal side by Wnt/βcat signaling, and a currently unidentified factor may be required for the induction of squint and cyclops in ventrolateral regions. In addition, perduring maternal factors have essential roles within the nodal signaling pathway.

PROSPECTS AND CHALLENGES

As this review attempts to convey, many important insights have been provided by the analysis of maternal factors required for early embryonic development. However, our current knowledge represents only a patchy and superficial picture of the overall complexity of interactions occurring during oogenesis and in the early embryo. The cellular and molecular mechanisms that occur during oogenesis, which lay out the prepatterns on which the embryo will rely, such as the establishment of the animal–vegetal polarity of the egg, remain largely unknown. During early embryogenesis, although much progress has been made in better understanding major pathways involved in cell fate determination, most notably in dorsoventral patterning, many of the key players and interactions in these pathways remain to be discovered. Similarly, the plethora of cellular processes that support early development, from basic cellular functions such as fertilization and cell division to changes in organelle and cytoskeletal organization underlying the segregation of patterning determinants, are poorly understood. Other important fields of research will involve the transition from maternal to zygotic developmental control and how maternally derived factors interact with zygotic products to ensure fine-tuned and reliable developmental programs.

Several avenues are expected to gradually provide a more complete view of maternally controlled developmental pathways. The analysis of maternal-effect mutations identified in previous (Pelegri and Schulte-Merker, 1999; Pelegri et al., 1999; Dekens et al., 2003; our unpublished work) and ongoing maternal-effect screens (M. Mullins, personal communication) will continue to provide important clues on early developmental processes and how they depend on individual genes. Other technologies will undoubtedly make major contributions to these forward genetic approaches. In particular, the identification of maternal transcripts (whether ovary-specific or transcripts expressed more generally), combined with reverse genetic approaches such as target-selected gene inactivation (Wienholds et al., 2002) or the use of morpholino oligonucleotides to inhibit translation of specific mRNAs (Nasevisius and Ekker, 2000), will likely become a major strategy to determine the function of maternally provided factors. The development of methods to reduce the function of genes expressed during oogenesis, such as RNA interference in the oocyte using specific hairpin transgenes (Stein et al., 2003), could be instrumental to understand the function of genes during oogenesis as well as those early embryonic functions that rely on maternal protein and that are, therefore, resistant to morpholino oligos injected into early eggs. Further knowledge about maternal factors will also accumulate as the analysis of currently known mutants identified in zygotic screens (see for example, Driever et al., 1996; Haffter et al., 1996) continues and they are tested for maternal effects.

Thus, a variety of approaches promise to greatly increase our knowledge of the precise roles of maternal factors during oogenesis and early zebrafish development. It is likely that this effort will contribute substantially to our understanding of early developmental processes, in particular as applied to vertebrate species.

Acknowledgements

I thank Jamie Lyman-Gingerich and the referees of this manuscript for their helpful comments. Research in our laboratory is supported by a March of Dimes Birth Defects Foundation grant #5FY00-597 and an NIH grant R01 GM65303.

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Citing Literature

Volume228, Issue3

Special Issue:Zebrafish as a Model System

November 2003

Pages 535-554

Maternal factors in zebrafish development

Abstract

INTRODUCTION

GENERAL ASPECTS OF FISH OOGENESIS: PRODUCTION AND UPTAKE OF MATERNAL PRODUCTS

mRNA AND PROTEIN DISTRIBUTION DURING OOGENESIS AND THE ANIMAL–VEGETAL AXIS OF THE OOCYTE

Patterns of mRNA Localization During Oogenesis

Protein Expression and Localization During Oogenesis

REDISTRIBUTION OF MATERNAL PRODUCTS DURING EGG ACTIVATION

GENETIC NOMENCLATURE

GENERAL CELLULAR REQUIREMENTS DURING CLEAVAGE AND GASTRULATION

GERM PLASM IN ZEBRAFISH OOCYTES AND EMBRYOS

Segregation of mRNAs Present in the Germ Plasm

Regulation of Expression of Germ Plasm Products

MATERNAL FACTORS INVOLVED IN DORSOVENTRAL PATTERNING

Determination of an Axis-Induction Center by Wnt/β-Catenin Signaling

Wnt/Calcium Signaling May Down-regulate Dorsal Signals in Early Embryos

Ventral Pathway Dependent on Factors of the Bmp Family of TGF-β Ligands

ANTERIOR–POSTERIOR AXIS DETERMINATION

MATERNAL REQUIREMENTS FOR GERM LAYER SPECIFICATION

PROSPECTS AND CHALLENGES

Acknowledgements

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Maternal factors in zebrafish development

Abstract

INTRODUCTION

GENERAL ASPECTS OF FISH OOGENESIS: PRODUCTION AND UPTAKE OF MATERNAL PRODUCTS

mRNA AND PROTEIN DISTRIBUTION DURING OOGENESIS AND THE ANIMAL–VEGETAL AXIS OF THE OOCYTE

Patterns of mRNA Localization During Oogenesis

Protein Expression and Localization During Oogenesis

REDISTRIBUTION OF MATERNAL PRODUCTS DURING EGG ACTIVATION

GENETIC NOMENCLATURE

GENERAL CELLULAR REQUIREMENTS DURING CLEAVAGE AND GASTRULATION

GERM PLASM IN ZEBRAFISH OOCYTES AND EMBRYOS

Segregation of mRNAs Present in the Germ Plasm

Regulation of Expression of Germ Plasm Products

MATERNAL FACTORS INVOLVED IN DORSOVENTRAL PATTERNING

Determination of an Axis-Induction Center by Wnt/β-Catenin Signaling

Wnt/Calcium Signaling May Down-regulate Dorsal Signals in Early Embryos

Ventral Pathway Dependent on Factors of the Bmp Family of TGF-β Ligands

ANTERIOR–POSTERIOR AXIS DETERMINATION

MATERNAL REQUIREMENTS FOR GERM LAYER SPECIFICATION

PROSPECTS AND CHALLENGES

Acknowledgements

REFERENCES

Citing Literature

Figures

References

Related

Information