Human Molecular Genetics, 2000, Vol. 9, No. 6 945-951
© 2000 Oxford University Press
Zebrafish developmental genetics and central nervous system development
IGBMC, CNRS/INSERM/ULP, BP 163, 67404 Illkirch, France
Received 24 January 2000; Accepted 7 February 2000.
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ABSTRACT |
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The central nervous system (CNS) is the most complex tissue of vertebrates. Recently, the zebrafish has emerged as a powerful genetic system for studying early development, and large-scale mutagenic screens for embryonic patterning defects have been accomplished. Mutants isolated in these screens are proving helpful in unravelling the molecular hierarchies involved in the development of the CNS. We review here recent studies in zebrafish which shed light on the genetic pathways involved in induction and regionalization of the CNS.
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INTRODUCTION |
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The central nervous system (CNS) of vertebrates develops from a specialized region of the ectoderm, the neuroectoderm or neural plate, which is specified during gastrulation. Subsequently, this neural plate is transformed into a neural tube in a process known as neurulation. Most vertebrates use a folding mechanism in which the lateral edges of the neural plate come together and fuse at the dorsal midline of the tube. In contrast, the zebrafish neural plate is converted initially into a solid structure, the neural keel, which develops a neurocoel or central canal secondarily by detachment of cells in the centre. The neural keel forms in an anterior to posterior progression, and dye labelling experiments have shown that the mediolateral position of a cell in the neural plate is projected faithfully onto the dorsoventral axis of the neural keel (1,2). Cells will cross the midline during formation of the neural keel, however, so that descendants of individual neural plate cells will end up in both sides of the neural keel (1,3). In this respect, neurulation in the zebrafish resembles the secondary neurulation seen in the tail regions of higher vertebrates (4).
The first neurons become post-mitotic in the neural plate shortly after gastrulation, and before the transformation into the neural keel has started (5). As a consequence, embryos are already motile at the end of the first day of development, showing spontaneous twitching of the body axis. During the second day of development, the zebrafish embryo starts to respond to touch stimuli. This response is coordinated by relatively few differentiated neurons and a simple scaffold of pioneering axons (6–9) which relay touch inputs to muscle cells flanking the neural tube, eliciting the characteristic startle response required in the wild for escape (10).
The zebrafish so far is the only vertebrate organism subjected systematically to large-scale forward genetics. Several genetic screens focusing on embryonic and larval stages have been completed recently, providing >500 different mutations affecting development, including physiological processes such as motility and touch response. These enormous screening efforts have shown that zebrafish is a powerful genetic system, allowing the same non-biased approach to the study of gene function that has proven to be extremely powerful in the investigation of complex developmental processes during invertebrate development (11,12).
In this review, we will summarize the concepts underlying the early regionalization of the CNS with a particular focus being placed on zebrafish mutations that affect these processes (Table 1). Because of space constraints, we will not be able to include a treatment of axonogenesis but will concentrate on the mechanism underlying specification of the neuroectoderm, its subdivision into distinct domains and neurogenesis.
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SPECIFICATION OF THE NEUROECTODERM |
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Formation of the neural plate is associated intimately with the establishment of dorsoventral positional identity during gastrulation. Experiments by Spemann and Mangold (13) indicated that signals provided by dorsal mesoderm of the amphibian embryo induce ectoderm to follow a neural rather than an epidermal fate. Recently, however, it has been shown that ectodermal cells, which were dissociated and thus unable to receive inductive signals from neighbouring cells, adopt neural fates (14,15). These data suggest that the default state for the ectoderm is neural. Moreover, the proposed neuralizing signals emanating from dorsal mesoderm are likely to be antagonists of signals that promote epidermal fate.
At the molecular level, evidence suggests that the non-neural ectoderm-promoting signals are members of the bone morphogenetic protein (BMP) subfamily of the transforming growth factor-ß (TGF-ß) class of growth factors. Addition of BMPs to dissociated ectodermal cells induces an epidermal fate and blocks them from adopting a neural fate (15). In experiments in which BMP signalling is prevented by a dominant-negative BMP receptor, the opposite result is achieved; epidermal differentiation is inhibited and the neural plate is expanded (16–19). Confirmation of the endogenous requirement for BMP signalling in these processes has been provided by mutants in the zebrafish genes swirl and snailhouse which encode zebrafish homologues of BMP2 and BMP7, respectively. swirl and snailhouse homozygous mutants are characterized by an expansion of the neural plate at the expense of non-neural ectoderm (20–24).
Three candidates exist for the BMP-antagonizing, neuralizing signals: follistatin, noggin and chordin are capable of inducing neural tissue when injected into Xenopus. It has been shown that they antagonize BMP activity by binding BMPs directly and blocking interactions between BMPs and their receptors (25–30). Zebrafish orthologues are expressed dorsally during gastrulation, consistent with a function in neural induction (31–33). Furthermore, zebrafish embryos carrying mutations in the gene chordino, which encodes the zebrafish homologue of Xenopus Chordin, are ventralized in perfect agreement with a function as an antagonist of the ventralizing BMP signals (33). The chordino mutation, however, affects the development of the mesoderm more severely than that of the neuroectoderm; CNS development is retarded relative to non-mutant siblings but ultimately develops normally. It remains to be seen whether the lack of a pronounced neural phenotype in chordino mutants is due to redundancy with the other BMP inhibitors noggin and follistatin (31,32).
The gain-of-function studies in both Xenopus and zebrafish, together with the phenotype of the BMP2- and -7-deficient zebrafish mutants strongly support the default model of neural induction. However, whether a default mechanism of neural induction is also employed in higher vertebrates is under debate (34).
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REGIONALIZATION |
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Dorsoventral
The neural tube of zebrafish embryos is, like that of other vertebrates, highly polarized along its dorsoventral axis. In the spinal cord, sensory neurons form at dorsal aspects, whereas motor neurons and the floorplate develop at ventrolateral and ventral positions, respectively, and interneurons occupy intermediate regions (Fig. 1).
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Patterning of the neural tube along its dorsoventral axis is initiated during the neural plate stages. Initially, the mediolateral coordinates of the neural plate, corresponding later to the dorsoventral coordinates of the neural tube, are established by secretion of signalling molecules from non-neural tissue surrounding the neural plate (35). An important organizing centre of the ventral neural tube is the axial mesoderm which is comprised of notochord and prechordal plate mesoderm and which underlies the midline of the neural plate. A second organizing centre, the floorplate, subsequently is established in the ventral neural tube itself as a consequence of the action of signals derived from the axial mesoderm. Sonic hedgehog (Shh) is one of several vertebrate homologues of the Drosophila hedgehog gene product, the founding member of this family of secreted molecules, and is expressed sequentially in the axial mesoderm and then in the floorplate. Shh has been shown to induce medial/ventral cell fates such as floorplate and motor neurons in amniote embryos (36–39).
As in higher vertebrates, the floorplate occupies the ventral- most aspects of the neural tube in zebrafish embryos and forms a continuous band of cells from the tip of the tail to the zona limitans of the diencephalon. The zebrafish floorplate is proposed to consist of two cell types, a medial row of cells and two lateral rows of cells. These two components of the floorplate can be distinguished by gene expression and by the genetic loci required for their formation. The medial floorplate cells express sonic hedgehog and the closely related tiggywinkle hedgehog gene, whereas certain members of the winged-helix transcription factor family are expressed in cells of both the lateral and medial floorplate (40–43).
Components of the Shh signalling pathways have been hit in the zebrafish mutant screens. The zebrafish shh orthologue is named sonic-you (syu) (44). In comparison with mouse embryos, the syu phenotype is very mild in the neural tube of zebrafish embryos as the medial floorplate and motor neurons appear to form normally; lateral floorplate cells, however, are missing in syu mutants. Mutations in you-too (yot), which encodes the zebrafish orthologue of the zinc finger transcription factor Gli2 and transduces Shh signals, do not appear to affect development of the floorplate at all in zebrafish embryos (45). In contrast, mouse embryos homozygous for loss-of-function alleles in this gene fail to form the floorplate (46,47). The apparent lack of phenotype in embryos carrying mutations in the Shh signalling pathway could reflect a fundamentally different mode of ventral neural tube specification in zebrafish embryos in comparison with amniotes, but this is unlikely. Most probably, the lack of phenotype is an indication of redundant gene functions in the zebrafish genome. Indeed, Postlethwait et al. (48) have provided evidence that the zebrafish genome is partially tetraploid due to a genome duplication that occurred at the beginning of the teleost radiation. Other mutations have been isolated that exhibit similar phenotypes to those of syu and yot and, thus, may encode partially redundant members of the Shh signalling pathway (49).
In contrast to mutations in syu and yot, with their moderate neural tube phenotypes, mutations in members of the nodal pathway have a severe impact on ventral neural tube development. Mutations in the cyclops (cyc) gene, which encodes a nodal-related protein of the TGF-ß family, abolish the medial floorplate whereas the lateral floorplate and motor neurons develop normally (40,50–52). As the name suggests, mutations in cyc are cyclopic and display deficiencies in ventral brain development, a phenotype resembling the human holoprosencephaly syndrome. Although no direct action for nodal signals in ventral neural tube development has been shown, these results suggest that nodal-related factors are required for specification of the floorplate and ventral brain. The cyc phenotype is strongly enhanced by mutations in a second nodal-related gene, squint (sqt); cyc/sqt compound mutant embryos not only have deficiencies of the ventral neural tube but also lack mesoderm and endoderm (53). A third locus resulting in cyclopic embryos is one-eyed pinhead (oep) (54,55). The oep gene was the first zebrafish gene to be cloned positionally and encodes a member of the CFC family of membrane-bound epidermal growth factor (EGF)-like proteins (56). Recently, it has been shown that embryos lacking both the maternal and zygotic function of the gene oep display a phenotype very similar to the cyc/sqt double mutant. In keeping with the similar phenotype, Oep recently was shown to be a component of the Nodal signalling pathway where it is required for cells to respond to Cyc and Sqt signals (57).
In amniotes, two members of the BMP family, BMP4 and -7, are secreted from the non-neural ectoderm flanking the neural plate/tube and have been implicated in the induction of lateral (neural plate) or dorsal (neural tube) fates (58). In agreement with such a role, inhibition of BMP function by expression of the BMP antagonist chordin (P. Blader and U. Strähle, unpublished data) abolishes differentiation of Rohon-Beard sensory neurons in the neural plate of zebrafish embryos, and the swirl (BMP2b) mutant displays defects in sensory neuron and neural crest development (24,59). Mutations in the narrowminded gene (nrd) result in the loss of Rohon-Beard sensory neurons from the dorsal neural tube and impair, only transiently however, neural crest cell development, suggesting a role for nrd in the establishment of dorsal neural tube identity (60). Whether nrd lies in the BMP pathway remains to be seen.
The homeobox gene floating head (flh) and the as yet molecularly uncharacterized masterblind (mbl) gene regulate neurogenesis in the dorsal diencephalon (61,62). Mutations in either of these two genes cause complementary phenotypes in the forebrain: whereas flh mutants fail to generate epiphysal neurons after the 18 somite stage, mbl mutants display a massive overproduction of these neurons throughout the dorsal forebrain. In situ RNA expression analysis suggested, furthermore, that mbl normally inhibits flh expression in this region (62). Thus, mbl appears to be a negative regulator of flh and the two genes seem to provide a link between regional specification and neurogenesis in the dorsal diencephalon.
Anteroposterior
From ablation and tissue recombination experiments, the organizer has been proposed to play a crucial role in anteroposterior patterning of the vertebrate CNS (63, and references therein). However, there is increasing evidence that tissues other than the organizer contribute to this process. In the mouse, the anterior visceral endoderm is a crucial source of forebrain-inducing signals (64). Increasing evidence suggests that the extraembryonic yolk syncytial layer (YSL) of the zebrafish embryo is homologous to the anterior visceral endoderm of the mouse (64,65). Indeed, mutations in the gene bozozok (boz) impair forebrain development; boz encodes a homeobox transcription factor (66), also known as dharma or nieuwkoid (67,68), which is expressed in the dorsal YSL. The anteroposterior pattern of the CNS in the zebrafish also appears to be laid down as a differential competence to respond to neural inducing signals in the entire epiblast comprising both neural and non-neural ectoderm. (69).
Recently, using a fine-scale ablation/transplantation ap- proach, it has been shown that the patterning of the anterior zebrafish brain depends on signals from a small population of anterior ectodermal cells at the interface between neural and non-neural tissue; removal of these cells leads to loss of forebrain character, and increased cell death and transplantation of these cells to more posterior regions induces the expression of anterior-specific brain markers (70). Similarly, signals from paraxial mesendodermal cells were shown to transform the zebrafish forebrain into hindbrain (71,72). Although several loci have been isolated that affect patterning of the forebrain and hindbrain, no mutant phenotypes have been reported that recapitulate these ablation and tissue recombination experiments.
Mutations have been isolated, however, that disrupt the formation of defined anteroposterior position identities. For instance, mutations in acerebellar (ace) and no-isthmus (noi) block the establishment of the boundary between the midbrain and hindbrain (73). ace and noi encode Fgf8 and Pax2.1, respectively (74,75). A third locus, spiel-ohne-grenzen (spg), results in a similar phenotype when mutated; spg has yet to be characterized molecularly (73). valentino (val) mutations affect hindbrain segmentation and result in a shortened hindbrain. Rather than generally interfering in hindbrain segmentation, however, val mutations specifically impair the formation of the fifth and sixth rhombomeres in a cell-autonomous manner. The val gene was cloned by homology on the basis of the similarity in phenotype with the mouse segmentation mutant kreisler which encodes a bZIP transcription factor (76,77).
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NEUROGENESIS |
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Neurogenesis is best understood in Drosophila (78). In the fruit fly, the neuroectoderm contains groups of cells, so-called proneural clusters, from which individual precursors are singled out to develop as neurons through a process known as lateral inhibition (79). Proneural clusters are characterized by expression of proneural genes such as achaete–scute and atonal which belong to the basic helix–loop–helix (bHLH) family of transcriptional regulators (80,81), and mutations in these genes lead to a reduction in the number of neurons. These transcription factors control the expression of the neurogenic gene Delta (82). Evidence suggests that high levels of Delta expression in one cell of a proneural cluster lead to the activation of the Notch signalling pathway in neighbouring cells. Activation of Notch results in repression of the proneural genes and a concomitant decrease in Delta expression, and thus drives cells into an epidermal differentiation programme (83). Conversely to the proneural genes, mutations in Notch or Delta block lateral inhibition and lead to an overproduction of neurons.
The mechanisms leading to the establishment of neuronal fate are less well understood in vertebrates. The presence of genes homologous to Notch and Delta as well as to achaete–scute and atonal suggests, however, that similar mechanisms of neurogenesis may exist in vertebrates and flies (84–86). Overexpression of neuroD or neurogenin, vertebrate homologues of the Drosophila proneural gene atonal, leads to the formation of ectopic neurons in zebrafish and Xenopus embryos, suggesting that these genes behave to some degree as the Drosophila proneural genes (87–89). Furthermore, the expression pattern of vertebrate Delta homologues within the neural plate suggests that a process similar to lateral inhibition acts within the neuroectoderm of the vertebrate embryo to single out particular cells to develop into neurons (90,91). Accordingly, misexpression of Delta results in inhibition of neurogenesis in zebrafish and Xenopus embryos (91–95).
The complexity of the neuronal types in the neural tube makes drawing parallels between Drosophila and zebrafish mutant phenotypes difficult, but there are some hints that genes whose phenotype resembles that of fly proneural or neurogenic genes exist in the fish. Mutations at the white tail (wit) locus result in a ‘neurogenic’ phenotype in which embryos display increased numbers of primary neurons at the expense of later developing neurons, radial glial cells and neural crest-derived pigment cells (96). Similarly, a mutation of the deltaA (dlA) locus has been isolated that leads to a neurogenic phenotype (97). The phenotype of the mutant allele, which carries a single amino acid substitution in the second EGF repeat of the DeltaA protein, is more severe than a homozygous deletion of the locus, suggesting that the mutated protein acts as a dominant negative and interferes with the function of other Delta family members during zebrafish neurogenesis.
Zebrafish mutations have also been reported that affect the differentiation of specific subsets of neurons. For instance, most cranial motor neurons fail to develop in embryos homozygous for the mutation detour (dtr) (98). This failure to develop is not thought to represent a general failure in neurogenesis, however, as the expression of the neural determination gene neurogenin1 is unaffected. Another example of a mutation which affects only a subset of neurons may be the above-mentioned narrowminded (nrd) gene (60). Using an in situ hybridization/immunohistochemistry-based screen, Guo et al. (99) identified five genetic loci that affect the commitment and differentiation of catecholaminergic neurons. Further analysis of one of these mutations, soulless (sou), revealed that it encodes the zebrafish homologue of the homeobox transcription factor Phox2a (100).
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CONCLUSION |
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It has taken almost 20 years since the late George Streisinger first proposed the zebrafish as a useful model for developmental biology, but the isolation and analysis of a significant number of mutations in the zebrafish in the last few years has proved him right. In such a short time, the zebrafish has already provided a wealth of information even with many mutants having been analysed only superficially at the phenotypic, let alone the molecular, level. There is a lot more to come, especially as screening continues with more sophisticated methods, and the mapping and cloning efforts will identify more and more of the genes altered by mutations.
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ACKNOWLEDGEMENTS |
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We are supported by the Institute National de la Sante et de la Recherche Medicale, the Centre National de la Recherche Scientifique, the Centre Hospitalier Universitaire Regional, ARC, AFM and La Ligue contre le Cancer.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +33 3 88 65 33 56; Fax: +33 3 88 65 32 01; Email: blader@igbmc.u-strasbg.fr
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