Invertebrate versus vertebrate neurogenesis: Variations on...

DEVELOPMENTAL GENETICS lfk1-10 (1996)

REVIEW ARTICLE

Invertebrate Versus Vertebrate Neurogenesis: Variations on the Same Theme? AD1 SALZBERG AND HUGO J. BELLEN Howard Hughes Medical Institute, Department of Molecular and Human Genetics, Division of Neuroscience, Baylor College of Medicine, Houston, Texas

INTRODUCTION The morphology of a vertebrate body appears very

different from that of, for example, a worm or a fly. However, it has become obvious from molecular, genetic, and developmental studies that this apparent di- versity does not necessarily reflect fundamental differences in the molecular mechanisms that underlie pattern formation in these different species [for review, see Laufer and Marigo, 19941. Indeed, many gene products that are conserved in structure and function throughout evolution have been identified and the animals that we study seem more similar every day [for review, see Bodmer, 1995; Laufer and Marigo, 1994; Littleton and Bellen, 1995; Bonhoeffer and Sanes, 19951. Most recently, another striking example was added to a fast growing list of genes, as the Drosophila eyeless gene and its mammalian homologues Small eye/ Aniridia play similar key roles in eye development of fruitfly, mouse, and human [for review, see Hanson and Van Heyningen, 1995; Halder et al., 19951. Here, we review and compare recent knowledge about the molecular mechanisms underlying nervous system development in vertebrates and invertebrates.

The molecular mechanisms that underlie early neurogenesis have been best characterized in Drosophila [for review, see Hassan and Vaessin, 1996 (this issue); Schweisguth et al., 1996 (this issue)] and C . elegans [for review, see Duggan and Chalfie, 1995; Sengupta and Bargman, 1996 (this issue)]. In recent years, homologues of many invertebrate genes involved in neurogenesis have been cloned in vertebrates [for review on vertebrate neurogenesis, see Calof, 1995; Kuwada, 1995; Groves and Anderson, 1996 (this issue)l, and it is now possible to initiate a critical and more systematic comparison of neurogenesis in these different phyla. This review focuses mainly on a comparison of neuronal determination and early differentiation in the peripheral nervous system (PNS) of invertebrates (flies and worms) and vertebrates (mice, chicken, zebrafish). The PNS is a more tractable system than the central

nervous system (CNS) due to its simpler structure; our knowledge about PNS development is therefore more advanced. However, it should be noted that many of the genes that are involved in the development of the PNS are also involved in CNS development [A. Salzberg and H. Bellen, unpublished data]; hence the separation of CNS versus PNS is somewhat arbitrary.

The PNS of worms, flies, and mice differ consider- ably in their anatomical features, In C. elegans, most neurons are generated in reproducible positions in the periphery. They arise from invariant cell lineages, and cell ancestry determines their fate [reviewed by Sul- ston, 19881. The strict classification into sensory receptors, inter neurons, or motor neurons is often not possible in C. elegans because single neurons can combine several functions [Ward, 19751. However, a mature PNS organ or sensillum (mechano- and chemoreceptors) consists of three or more peripherally located cells: a neuron (or set of neurons) ensheathed by a sheath cell (glia-like cell), and a socket cell that sur- rounds the shaft of the dendrite(s) [Perkins et al., 19861. The precise function of many sensilla is un- known but some have specialized dendritic projections beneath the cuticle and may mediate mechanosensa- tion. Others communicate with the outside through a hole in the cuticle and are thought to function as chemoreceptors [reviewed by Chalfie and White, 19881. The cells of a single sensillum are closely related by

Received for publication September 7, 1995; accepted September 11, 1995.

Address reprint requests to Dr. Hugo J. Bellen, Howard Hughes Med- ical Institute, Department of Human and Molecular Genetics, Divi- sion of Neuroscience, Baylor College of Medicine, Houston, TX 77030.

Dr. Salzberg is now at the Department of Genetics, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.

0 1996 WILEY-LISS, INC.

2 SALZBERG AND BEUEN

lineage [for examples, see Figure 1 in Sengupta and Bargman (this issue)]. In addition to the sensilla, there are three touch receptor neurons in C . elegans that are not organized as sensilla and that have multiple den- drites [Chalfie and White, 19881. These neurons control the response of the worm to touch. A simple touch as- say has been used to isolate mutants that respond ab- normally to touch [for review, see Duggan and Chalfie, 19951. Other screens that focused on cell lineages have also allowed identification of mutations that affect PNS development [for review, see Chalfie and White, 19881.

The PNS of the fruitfly embryo is somewhat similar to that of the worm. Most notably, the cell bodies of the neurons are located in the periphery (unlike many neurons of the PNS in vertebrates), and many sensory organs consist of few cells, e.g., a neuron, a sheath or glial associated cell, and two other accessory cells. The lineages of the different PNS organs in Drosophila embryos have recently been reanalyzed and are reviewed by Brewster and Bodmer (this issue). A sensory organ precursor cell divides twice or thrice to give rise to several cells which constitute a sensory organ (see Figs. 1-2, in Brewster and Bodmer). Different types of sensory organs are thought to play a role in mechano-, chemo-, or stretch transduction. In addition, as in the worm, the PNS of the fly contains multiple dendritic neurons that are not associated with sensory organs and may be involved in touch perception.

The PNS of adult flies is more elaborate than the embryonic PNS. However, as in embryos and larvae, the adult PNS consists of a stereotyped array of sensory organs. The molecular mechanisms directing the ontogeny of embryonic and adult sensory organs are prob- ably quite similar, although clearly not identical [for review, see Jan and Jan, 19931. Adult flies, like most insects, are covered with bristles secreted by hair cells. These cells are part of external sensory organs which most often function as mechanoreceptors. Morphologi- cal changes of these hairs are easily identifiable and many genes that affect the PNS in the fruitfly were isolated on the basis of altered bristle patterns in adult flies (e.g., achaete, scute, Hairless, extra macrochaetae; see Lindsley and Zimm, 19921. More recently, genes involved in PNS development were isolated primarily because they are expressed in the PNS cells or their precursors (e.g., prospero, tramtrack) [Vaessin et al., 1991; Guo et al., 19951. Systematic searches to identify genes based on phenotypic alterations in embryos or larvae have only been carried out fairly recently [Salzberg et al., 1994; Kania et al., 19951.

The anatomical features of vertebrate PNS are quite different from those of invertebrates. The cell bodies of PNS neurons involved in touch, cold, pain, and pro- prioception are not positioned in the periphery as de- scribed for invertebrates, but are grouped in the dorsal ganglia along the spinal cord. This is obviously not the case for all the neurons of the PNS in vertebrates as the

cell bodies of photoreceptors, chemosensory neurons and auditory neurons are situated peripherally, as is also the case in insects. A substantial portion of the vertebrate PNS neurons arise from the neural crest prior to closure of the neural tube. These neurons migrate laterally and populate the dorsal root ganglia where they send out neurites to the periphery, Re- cently, Sharma et al. (1995) showed that a second mi- gratory wave of PNS neurons takes place from the dorsal tube, long after the primary migration from the neural crest. These neurons migrate from the dorsal side of the neural tube via the dorsal root into the dorsal ganglia, where they join the neurons that previously migrated there from the neural crest. Hence, the ontogeny and anatomical features of the mature vertebrate PNS appear quite different from those of invertebrates. Relatively little is known about the molecular mechanisms underlying vertebrate PNS development, and genetic approaches to isolate genes that affect PNS development have not been feasible in vertebrate species until recently. The work presented by Henion et al. (this issue) is a first in this respect.

SIMILAR GENES, SIMILAR DEVELOPMENTAL PATHWAYS?

Many vertebrate genes exhibiting structural similarity to Drosophila genes required for neuronal determination, differentiation, and growth cone guidance have been identified in recent years. Table 1 lists Dro- sophila genes known to be involved in neurogenesis and their homologues identified in other species, Ow- ing to space limitations, this Table corresponds only to some aspects of neurogenesis and does not include pre- pattern genes [Patel et al., 1989; Condron et al., 19941 and genes required for growth cone guidance, fascicu- lation, and synaptogenesis [Kolodkin et al., 1993; for reviews, see Goodman and Shatz, 1993; Goodman, 1994; Fernandes and Keshishian, 1995; Muller and Kypta, 19953. The sequence conservation found between Drosophila genes and their vertebrate cognates suggests that vertebrate and invertebrate animals share at least some of the mechanisms that control neurogenesis. Recently, in vivo evidence to support the involvement of three vertebrate homologues, MASHI, X-Deltal, and X-Notchl, in neurogenesis has surfaced. Similar data are still lacking for most vertebrate homologues (e.g. MATH-1 [atonal] CDP, Cux [cut]), but this may change rapidly, given the speed at which targeted mutations in mice are being generated.

SIMILAR SEQUENCES, SIMILAR ROLES? In the simplified model shown in Figure 1, the onset

of neurogenesis is marked with the specification of neuronal precursors. In Drosophila, the precursors of both the PNS and CNS emerge from domains of ectodermal cells termed proneural clusters. All the cells in the cluster that express the proneural genes are competent

INVERTEBRATE VS VERTEBRATE NEUROGENESIS 3

TABLE 1. C. ekgans and Vertebrate Homologues of Dmsophila Genes Implicated in Neurogenesis

Drosophila genes involved in neurogenesis and homologues from other species (% identity) Putative roles and functions References Positive regulators of neurogenesis

achaete and scute

Xenopus XASH-1 and 3

Zebrafish ZASH-la, -1 b Chicken CASH-1 Mouse and rat MASH-l ,2 (80% in

HLH domain)

Human hASHl(80% in HLH

atonal domain)

C . elegans Zin32 (63% in bHLH domain)

Mouse MATH-1 (70% in bHLH domain)

daughterless

Chicken GbHLH1.4 (76% in bHLH

Human E12/E47 (76% in bHLH domain)

domain)

(lateral inhibition) Negative regulators of neurogenesis

Notch

C . elegans lin-12 C . elegans glp-1

Xenopus X-Notch-1 (47% overall, 51% in EGF-like repeats, 70% in cdclO repeats)

Zebrafish Notch Mouse Notch 1 , 2 , 3 ;

int-3

Rat Notch 1 , 2 (47% overall, 51% in EGP-like repeats, 70% in cdclO domain)

Human Notch 1 , 2 , 3

Proneural genes for external sensory

Activates neural gene expression,

organs

promotes neurogenesis and causes neuronal hyperplasia when ectopically expressed

ND ND Mczsbl -I- mice exhibit loss of

neurons, mainly from the olfactory epithelium and sympathetic ganglia

ND

Proneural gene for chordotonal organs and pbotoreceptors

Specifies neuroblast cell fate; loss of function causes loss o f sensory organs

Activates E-box-dependent transcription in collaboration with the daughterless homologue E47

neurons; Da can form heterodimers with AS-C proteins

Loss of da removes all peripheral

ND

Bind as dimers to E-boxes

Receptor in lateral signaling and other inductive signals

Function as receptors in cell-cell interactions which specify cell fates (in a manner analogous to Drosodda - Notch)

May inhibit differentiation and keep undetermined cells comDetent for receiving inductive signals. Expression of activated Notch causes neural and mesodermal hypertrophy and loss of dorsal structures.

ND Mice lacking one of their Notch genes

die as embryos and exhibit extensive regions of cell death

Expression of activated int-3 in transgenic mice leads to lack of differentiation and hyperproliferation of glandular epithelia

Notch-1 (also called TAN-1) truncation is related to tumor formation. Notch-2 and 3 also map to chromosomal regions of

Cabrera et al., 1987; Villares and Cabrera, 1987; reviewed by Campuzano and Modolell, 1992

1993; Ferreiro et al., 1994 Zimerman et al., 1993; Ferreiro et al.,

Allende and Weinberg, 1994 Jasoni et al., 1994 Johnson et al., 1990; Guillemot et al.,

1993; Lo et al., 1991; reviewed by Joyner and Guillemot, 1994; Franco del Amo et al., 1993

Ball et al., 1993

Jarman et al., 1993, 1994, 1995

Zhao and Emmons, 1995

Akazawa et al., 1995

Caudy et al., 1988a,b

Helms et al., 1994

Murre et al., 1989

Wharton et al., 1985; reviewed by Artavanis-Tsakonas and Simpson, 1991; Heitzler and Simpson, 1993; Artavanis-Tsakonas et al., 1995

Greenwald et al., 1983; Yochem and Greenwald, 1989; Austin and Kimble, 1989; reviewed by Greenwald and Rubin, 1992; Mello et al., 1994

Coffman et al., 1990, 1993

Bierkamp and Campos-Ortega, 1993 Gallahan et al., 1987; Robbins et al.,

1992; Franco del Amo et al., 1992, 1993; Swiatek et al., 1994; Conlon et al., 1995

Jhappan et al., 1992

Weinmaster et al., 1991, 1992

Ellisen et al., 1991; Larsson et al., 1994

neoplasia-assocked translocations (continued)

4 SALZBERG AND BELLEN

TABLE 1. C. elegans and Vertebrate Homologues of Drosophila Genes Implicated in Neurogenesis (continued) ~

Drosophila genes involved in neurogenesis and homologues from other species (% identity) Putative roles and functions References

Mediates lateral sienalinp: through its Vassin et al.. 1987: Parodv and Delta

C. elegans lag-2 (another similar protein is apx-1 which is closer to the Drosophila Serrate protein)

Xenopus X-Delta-1 Chicken C-Delta-1 Enhancer of Split (and hairy)

Mouse and rat HES-1, HES3 HES-1 shows 70% and HES-3 50%

identity to hairy in the bHLH domain and only 40% to E(Sp1)

Suppressor of Hairless

Mouse RBP-JK (82%) Human RBP-JK (CBF1)

Neural identity genes cut

Dog Clox (48% in HD)

Mouse Cux (50% in HD)

Rat CDPP (50% in HD, -70% in CD)

Human CDPlcut

Newonal precursor genes Prosper0

C. elegans Dromero (79% in HD)

interaction with hotch.-hss ofyDl causes hyperplasia of the nervous system.

receptor A signaling ligand for the LIN-18

Mediates lateral inhibition ND Acts downstream of Notch in the

neurogenic pathway

Binds preferentially to N boxes. Persistent expression of HES-1 in mice perturbs neuronal and glial differentiation. HES-3 is expressed exclusively in cerebellar Purkinje cells

transcription regulator. Involved in the establishment of alternative cell fates

Sequence-specific DNA binding

Sequence-specific DNA binding Acts as a transcription regulator by

binding to specific DNA sites

Specifies external sensory organ - - identity

Shown to reoress MEF2-mediated cardiac myosin gene activation

Inhibits expression of neural cell adhesion molecule (NCAM) DNA binding

genes

promoter

Repressor of developmentally regulated

Represses transcription from c-myc

Regulates expression of neuronal precursor-specific genes

ND NlI

Muskavitch, 1993; Muskavitch, 1994

Tax et al., 1994; Henderson et al., 1994; Wilkinson et al., 1994

Chitnis et al., 1995 Henrique et al., 1995 Delidakis and Artavanis-Tsakonas,

1992; Knust et al., 1992; Jenings et al., 1994

Sasai et al., 1992; Takebayashi et al., 1994; Ishibashi et al., 1994; Sakagami et al., 1994

Furukawa et al., 1992; Schweisguth and Posakony, 1992, 1994

Matsunami et al., 1989 Brou et al., 1994; Dou et al., 1994; Hsie

and Hayword, 1995

Blochlinger et al., 1988

Andres et al., 1992

Valarche et al., 193

Yoon and Chikaraishi, 1994

Neufeld et al., 1992; Dufort and Nepveu, 1994; Lievens et al., 1995

Chu-lagraff et al., 1991; Vaessin et al., 1991; Doe et al., 1991; Matsuzaki et al., 1992

Burglin, 1994 Oliver c?t al.. 1993

to become neuronal precursor. However, only one or a few cells in each cluster are singled out to become neuronal precursors whereas the remaining cells adopt the epidermal fate. The binary switch between epidermal and neuronal fate has been extensively studied in embryonic and adult PNS, and many of the genes that function as positive and negative regulators of neurogenesis have been identified. As shown in Table 1 (and references therein), many of these genes have been conserved during evolution, and many mammalian cognates have been identified. Nevertheless, the function of a single gene, or a discrete molecular event specified by the action of a small group of genes, is in a way a modular unit that can be used differently in different

developmental contexts. Thus, conservation of amino acid sequences does not necessarily imply conservation of developmental role. Similarly, the same protein may function in different developmental pathways in different tissues of the same organism. In addition, vertebrate genes have diverged during evolution, and often multiple genes with sequence similarity can be identified for a given Drosophila gene (e.g., AS-C, Notch). Thus, it is necessary to determine in each case which of the vertebrate homologues exhibit functional homology to the Drosophila gene and how similar their roles are. Recent knockout experiments in mice and in vivo manipulations of Xenopus oocytes [for review, see Joy- ner and Guillemot, 1994; Calof, 19951 provide an op-


Drosephila PNS YeaQkmb neuroaenesis Drosonh& common lx&lm-&

eeneS homologues mXEs Patterning and regionalization Prepatteming

" . ^__I"- L "- ~ ~___- Neural competence

Selection of neural precursors

Maintenance of neural determination

Early, pan-neural differentiation

t

t

1 1

Sensory organ Identity

Cell division and cell fate determination

I

Terminal differentiation and survival

A (including axogenesis and s ynaptogenesis)

MASHI

Notch1 8 Delta-I 0 C-ret

@ CNTF

Neural detemination

1

Early differentiation and proliferation

I

Terminal differentiation and survival

Fig. 1. Steps in Drosophila and vertebrate neurogenesis. Sche- matic diagram depicting the different stages of PNS development in Drosophila (leftmost column) and vertebrates (rightmost column). Drosophila genes implicated in neurogenesis are listed near the developmental stage in which they are thought to be involved (open and

shaded rectangles). Vertebrate genes that were implicated in neurogenesis based on their mutant phenotypes are listed near the earliest developmental step for which they are thought to be required (el- lipses). Drosophila genes for which vertebrate homologues have been identified are shaded in gray.

portunity to assess the roles of several Drosophilu and C . elegans homologues in vertebrate neurogenesis. Data from these experiments hint toward a conserved mechanism that specifies neuronal precursors in flies and vertebrates. However, a t the same time, these experiments shed light on possible differences that exist in the hierarchylcascade of gene interactions that underlie this process in the different species. A few examples are discussed below.

CONSERVED ROLE FOR THE PRONEURAL GENES?

The Drosophilu proneural genes, the genes of the achuete-scute complex (AS-C) and atonal, are basic helix-loop-helix (bHLH) transcription factors that function as positive regulators of neuronal determination [Campuzano and Modolell, 1992; Jarman et al., 19931. Loss-of-function mutations in these genes cause a loss


of specific sensory organs, whereas ectopic expression leads to overproduction of sensory organs [Campuzano et al., 1986; Rodriguez et al., 1990; Jarman at al., 19931. The bHLH domain of the achaete-scute genes is highly conserved and achaete-scute homologues have been identified in fish, amphibians, avians, and mammals, atonal homologues have recently been identified in mouse and nematodes (see Table 1 and references therein). Phenotypic analysis of loss-of-function mutations and overexpression of the nematode atonal homologue, lin-32, demonstrate that the 11.32-32 gene product is necessary and sufficient for the specification of neuroblast versus epidermal fate [Zhao and Emmons, 19951. As was previously demonstrated for the AS-C and atonal genes in flies, loss of lin-32 function causes loss of sensory organs in the worm, whereas overexpression leads to the formation of ectopic sensory organs.

Expression studies of the mammalian AS-C homologues MASH-1 and MASH-2 revealed that MASH-1 is expressed specifically in the developing nervous system [Johnson et al., 19901. Detailed analysis of MASH-1 expression in mouse embryonic PNS revealed early expression in neural crest cells as they arrive at sites of peripheral neurogenesis [Lo et aE., 1991; Guillemot et al., 1993; reviewed by Groves and Anderson, 1996 (this issue)]. The expression of MASH-1 in the PNS is restricted to precursor cells of the autonomic lineages and its transient pattern (it appears prior to markers of differentiated neurons and is down-regulated shortly after their appearance) is reminiscent of that of AS-C genes in the fly. MASH-1 -I- mice die shortly after birth and exhibit neuronal hypoplasia which correlates well with the expression pattern of the gene. These mice lack olfactory, sympathetic, parasympathetic, and en- teric neurons. The expression pattern of MASH-1 and phenotypes associated with its loss of function suggest an early role in neurogenesis, similar to that of the Drosophila AS-C genes.

In the absence of proneural genes in Drosophila, neuronal precursors fail to differentiate and expression of neuronal markers is abolished in affected neuronal lineages. However, recent data show that some markers such as snail [Ip et al., 19941 and scute [Vaessin et al., 19941, are expressed in neuroblasts or SOPS, even in the absence of some proneural genes. These data place the achaete-scute genes somewhere at the top of the hierarchy of genes required for neural determination/ differentiation but also suggest that an as yet unchar- acterized set of genes is involved in the specification of neuronal precursors. This may be quite similar to what has been observed in MASH-1 mutant mice in which several neuronal markers continue to be expressed by undifferentiated cells derived from the neural crest [Groves and Anderson, 19961. These data also suggest that more than one pathway of gene interactions gov- ern neuronal differentiation in neural crest cells and that gene(s) other than MASH-1 play a role in its

regulation. Whether these yet unidentified regulators function higher in the hierarchy of gene interaction, or function in parallel to MASH-1 or the AS-C genes, is currently an open question.

NEGATIVE REGULATORS OF NEUROGENESIS

All the cells in a proneural cluster express the AS-C genes (or ato) and are considered equipotent in their ability to become neural precursors. In a second phase, one or a few cells in the cluster accumulate higher levels of the proneural protein and start expressing neuronal precursor-specific markers. The gradual re- finement of proneural gene expression pattern, and the consequent selection of a single precursor cell, are mediated through cell-cell communications between the cells of the proneural cluster. This signaling process is referred to as lateral or mutual inhibition [Ghysen et al., 19931 or lateral specification [Artavanis-Tsakonas, 19951 and is mediated by the products of the genes of the neurogenic group. Loss-of-function mutations in the neurogenic genes lead to a neuronal commitment of all or most cells of the proneural cluster.

Two of the neurogenic genes, Delta and Notch, encode, respectively, a cell surface ligand and its receptor. These proteins mediate some key steps in lateral signaling in Drosophila. Cells expressing Delta activate Notch in neighboring cells. This inhibits the cells that receive the signal from becoming neural precursors. Recently, many vertebrate homologues of Notch have been cloned (see Table l), but the roles of the corre- sponding Notch proteins are still unclear. Targeted dis- ruption of Notch-1 in mice has neither confirmed nor disproved a role of Notch in vertebrate neurogenesis [Swiatek et al., 1994; Conlon et al., 19951. A truncated form of Notch lacking the extracellular domain (which functions in Drosophila as a constitutively active protein [Fortini et al., 19931) suppresses neurogenesis when expressed in PC12 cells, as expected [Nye et al., 19941. However, overexpression of a similar Notch protein in Xenopus causes an increase in neural tissue and muscles [Coffman et al., 19931. Hence, it has clearly been difficult to ascertain the role of Notch proteins in vertebrate neural development.

Recently, Chitnis et al. [19951 and Henrique et al. t19951 have provided evidence that vertebrate Notch and Delta play a similar role in neural development as their homologues in invertebrates. Injection of X-Delta mRNA inhibits production of primary neurons, and in- terfering with Delta activity by using an antimorphic X-Delta gene stimulates neurogenesis. In addition, in contrast to the results obtained by Coffman et al. [1993], injection of an activated X-Notch suppresses neurogenesis. On the basis of these results, Chitnis et al. [19951 propose that the “DeltalNotch signaling pathway is a universal device for controlling fine- grained patterns of cell differentiation in animal tis-


sues.” This suggests that the other genedproteins that are involved in this cascade in Drosophila (e.g., Sup- pressor of Hairless, Hairless, and genes of the E(Sp1) complex) are also likely to play a similar role in vertebrates. Indeed, as shown in Table 1, homologues of some of these genes have been identified. However, de- spite the conservation of molecular features [Brou et al., 1994; Tannahill et al., 19951, genetic or other in vivo evidence to support the role of these genes in vertebrate neurogenesis is still missing.

Finally, it should be noted that many important questions remain to which no satisfactory answers can be formulated at the present time. For example: why is the position of SOP in the proneural cluster so highly stereotyped? Are proneural cell clusters really domains of equivalent cells, or do some cells have more potential than others to become SOPS? Do Delta/Notch amplify a pre-existing difference between competent but not equipotent cells? How does Notch transduce the signal (binding of Delta) to the nucleus? Hints to some of these answers can be found in the reviews of Schweis- guth and colleagues and Hassan and Vaessin (this issue).

SELECTOR GENES AND GENES REQUIRED FOR NEURONAL DIFFERENTIATION

The lineages that give rise to different types of sensory organs in the PNS of Drosophila have been well characterized [for review, see Brewster and Bodmer (this issue)]. The stereotyped lineages and the avail- ability of numerous cell-type specific markers allowed the identification of selector genes required for the specification of correct cell identities in each step of the neuronal lineages. The cut gene encodes a homeobox protein, which is required to specify the identity of external sensory organs as a whole, and in its absence external sensory organs are transformed into chordotonal organs [Bodmer et al., 1987; Blochlinger et al., 19911. cut homologues have been identified in vertebrates (see Table 1 and references therein) and were shown to act as repressors of developmentally regulated genes such as the neuronal adhesion protein NCAM [Andres et al., 19921. However, as none of the vertebrate cut homologues has been manipulated in vivo, it is not known whether these homologues actu- ally affect cell identity in vertebrate neuronal lineages.

Many features are common to all PNS neurons. Thus, in addition to the lineage specific developmental programs, it is likely that a pan-neuronal program exists. These genes may confer a general neural identity to neuronal precursor cells and hence actively participate in the initiation or maintenance of neural differentiation. Several genes in Drosophila are thought to participate in this pan-neural developmental pathway. One of these genes is prospero. In the absence of the Propsero protein, neural differentiation is aborted, leading to profound defects in the nervous

system. Recently, Oliver et al. [19931 isolated the mouse homologue, Prox-1 and demonstrated that the Prox-1 message is found mainly in young post-mitotic differentiating neurons in the spinal cord and the brain, Based on the similar expression profiles in Dro- sophila and mice the authors suggest that both proteins may play similar roles. However, no other data on the in vivo function of Prox-1 have been published.

NEURONAL SURVIVAL Most if not all neurons in the mammalian nervous

system seem to depend on growth factors for their survival [for review, see Silos-Santiago et al., 19951. Neu- ronal numbers seem to be much larger early in development than late and many neurons are thus thought to die during development. Similarly, in invertebrates, neuronal death and apoptosis in the nervous system have been extensively documented [Hengartner and Horvitz, 1994; Steller and Grether, 1994; Zhou et al., 19951. The genetics of programmed cell death has been studied extensively in vertebrates and invertebrates and the mechanisms by which apoptosis occurs seem to rely on a similar basic molecular machinery [Hengart- ner and Horvitz, 19941. Yet, whereas the signals that induce apoptosis in the nervous system of vertebrates have been well documented, the signals that trigger cell death in the invertebrate nervous system are un- known. Many neurotrophic factors required for neuronal survival and their receptors have been extensively characterized in vertebrates (Fig. 1) [for review, see Silos-Santiago et al., 1995; Slack and Miller, 1996 (this issue)]. However, to our knowledge, none of these factors has known homologues in invertebrates. Hence, here may lie a basic difference between vertebrate and invertebrate neural development.

EPILOGUE This review has touched on the few known key as-

pects of neurogenesis that seem to be conserved between invertebrates and vertebrates. Some of the differences have been highlighted as well. The scope of this review is necessarily limited, and many topics such as cell cycle and the role of glia in nervous system development have not been covered. The review by Slack and Miller (this issue) provides an in depth cov- erage on the function of one of the key proteins that participate in the regulation of cell division in the CNS. Finally, the paper by Klambt et al. (this issue) illustrates the essential role of glia in the development of the CNS in Drosophila.

In summary, the preliminary data reviewed here suggest that major developmental pathways are conserved in PNS and CNS development of species as different as Drosophila and mouse. It is quite likely that a much clearer picture of the similarities between vertebrate and invertebrate nervous system development will emerge in the very near future. The next years


promise to be exciting and the interplay between vertebrate and invertebrate biologists promises to be fruit- ful. Comparative developmental biology is alive again.

ACKNOWLEDGMENTS We thank Maria Capovilla, Huda Zoghbi, and Karen

Schulze for comments on the manuscript. A.S. was a postdoctoral fellow from the HHMI. H.J.B. is a n asso- ciate investigator of the HHMI.

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