cellular and molecular biology of neural crest cell lineage determination

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T he development of the neural crest presents the challenging problem of how a migratory population of multipotential cells gives rise to a diverse array of differentiated derivatives. Because these derivatives include the neurons and glia of the peripheral nervous system (PNS), the neural crest also poses the problem of how different types of neurons are generated in development. For many years, the problem of neural crest devetopment was addressed primarily at the cellular level, using avian embryos as an experimental system’. More recently, it has become possible to ask questions about genes that control neural crest development, using the mouse, the chick and the zebrafish.

Neural crest cells detach from the neuroepithelium of the dorsal neural tube and migrate along a number of defined routes to various tissues, where they stop mov- ing and d&rent&e into various cell types (Fig. 1). These cell types exhibit diversity along the rostrocaudal extent of the neuraxis and also within a single axial level (Fig. 2). For example, crest cells that emigrate from the trunk region of the neural tube produce sensory and autonomic neurons of multiple subclasses, their associated glia, melanves in the skin and, in some regions, the endocrine cells (chromaffm cells) of the adrenal gland, while enteric neurons of the gut are generated from a specific position anterior to the trunk regionz.

The study of neural crest development at the cellular level has focused on the qut.,lion of how cell lineage and environmental influences control the gener- ation of these different cell types (reviewed in Ref. 3). At the initiation of migration, many individual neural crest cells are multipotent. The normal fate of these cells can be changed by transplanting them to different locations or by exposing them to different environments in uitro

Sympathetic neurons

Smooth muscle?

1

F#;uIIE 1. Derivatives of the neural crest in the trunk. A cross-xction through the trunk region of a mouse embryo is shown. Neural crest cells in this region are known to give rise to sensory and

autonomic (sympathetic or parasympathetic) neurons, Schwann @ial) cells and melanocytes. At other axial levels the crest

generates smooth muscle cells in certain blood vessels (Fig. 2). The contribution to the wall of the dorsal aorta is speculative and has not been observed in avian embryos.

Nevertheless, in mudne embryos a crest contribution to the smooth muscle of this blood vessel has not been excluded.

Abbreviations: DA, dorsal aorta; N, notochord; NT, neural tube.

Cellular and molecular biology of neural crest cell lineage determination

DAMD J. ANDEESDN

(reviewed in Ref. 4). The fact that neural crest cells are plastic and sensitive to their local environment raises several further questions. What is the identity of the environmental factors that influence crest ceil fate, what lineages do they effect, and what cells or tissues produce them? How do these factors affect the fate of multipotent cells? At one extreme, the choice of fate could be made by a cell-autonomous mechanism (either stochastic or deterministic) and the factors would support the survival or proliferation of lineage-restricted cells; at the other extreme, the factors could cause multipotent cells to choose one fate (or a subset of fates) at the expense of others. Which mechanism operates in the neural crest?

The fact that neural crest cells are initially multipotent and sensitive to environmental influences should not imply that lineage restrictions do not have a role in the deveiopment of the crest. IF post-migratory neural crest cells are transplanted back into the neural crest of younger host embryos, they generate some derivatives but not others5. This implies that neural crest cells gradually undergo restrictions in their developmental potential. However, it is not clear when and how restricted sublineages emerge, and why some derivatives are only produced from certain positions along the neuraxis. Furthermore, restrictions in developmental potential might occur randomly, sequentially, or accord- ing to some kind of hierarchy or pattern (e.g, Ref. 6). These issues, among others, are yet to be resolved.

The molecular gemtic problems of neural crest development

From one perspective, the problems of neural crest development at the molecular genetic level can be stated rather simply: what genes are important for neural crest development, and what do their products do? As in any developing system, these genes are likely to encompass growth factors and their receptors, signal transduction molecules and transcription factors. Indeed, there are already examples in each of these categories of genes that are essential for neural crest development. Genetic and biochemical analyses can allow, in principle,

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one to piece together pathways and networks that control the development of panicular cell types. What is more difficult is to understand how the action of these genes fits in with the lineage restrictions, positional dif- ferences and environmental influences on neural crest cell fate that have been revealed by cellular analysis_ In some cases, the relationships are straightfomfard: in others they are less so. Perhaps most challenging is the problem of how to explain changes in the developmental potential, or state of commitment, of neural crest cells, properties defined operationalIy by cellular experiments, in terms of the act!ons of specific genes.

In what follows, I briefly discuss selected experiments that begin to address some of the outstanding issues outlined above, focusing on work performed in mammalian systems where it has been possible to integrate cellular and molecular genetic approaches. Space limi- tations preclude a comprehensive survey of the extensive literature on neural crest development. In particular, this review emphasizes the development of lineages that arise from trunk neural crest (Figs 1 and 2). These lineages exclude bone and cartilage, which appear to rep- resent a developmental capacity unique to cranial neural crest*. The cranial neural crest is aIso intimatefy involved in pattern formation in the head and neck region’. While significant advances have recently been achieved in understanding thii patterning process (e.g. Reefs 8,9), a discussion of thii work is beyond the scope of this review. The reader is referred to recent review@-‘3 for further details.

Emc~~i~thatreglllak~crestlin~

Isolated mammalian neural crest cells are multiporent, self--renewing stem-like cells

Conditions for the growth of mouse and rat neural crest cells in clonal culture have been establishedl4*15. Such clonal assays have allowed several impomnt cell biological issues in neural crest development to be investigated: the developmental potential of these isolated mammalian neural crest cells; whether such cells can undergo self-renewal, like stem cells in other system&j; the environmental signals that influence the differentiation of these cells; and whether the signals act setectively or instructively.

In vitro, rodent neural crest cells are multipotent like their avian counterpart#,*s. In the rat, the cells have been shown to produce at least three differentiated cell types: autonomic neurons, glia and smooth muscle“W In the mouse, neurons, glia and melanocytes have been demonstrated to arise from single founder celW. The question of whether such isolated cells can also generate other crest derivatives, such as sensory neurons or cartilage20, remains open (although neurons expressing some sensory properties have been shown to develop in mass cultures of mouse neural crest21). Clonal analysis of avian neural crest cells, however, has provided evidence of such pleuripotency20.22, although not of self-renewal. The self-renewal of multipotent rat neural crest cells has been demonstrated by subcloning experiments*4. The properties of multipotency and self-renewal capacity are a characteristic of stem cells (reviewed in Ref. 161. Whether self-renewal of mammalian neural crest cells occurs irz Vito is not yet established, although

Cranial

Sansory rwrons Glia Melanocytes FacW bone/cartilage

7 Sensory neurons

Hindbrain

Vagal

Trllnk

Glia

Metanocytes Bone/cartilage

Smooti muscle Glia Melancqtes Enteric neurons Endocrine cells (thyroid)

Sensory neurons Glia Melanocytes Autonomic neurons Chromaffin cells Smooth muscle?

FIGURE 2. Variations in crest derivatives produced at different levels along the rostrocaudal extent of the neuraxis. Only major subdivisions of the neumxis and a simplified subset of crest derivatives are shown. The results are based primarily on fate-mapping experiments in avian embtyosl. (For a fuller description, see the monograph by k Douarinl.)

in avian embryos some multipotent cells can be recov- ered from peripheral tissues colonized by the neural crest (reviewed in Ref. 231, suggesting that self-renewal does occur.

Neural crest cellfates can be determiued Ly instruct& environmental signaLs in vitm

In the rat, three growth factors have been identified that bias the dserentiation of neural crest cells along dii tinct lineages: glial growth factor (GGF, a neuregulin2*~25), which promotes glial differentiatior@; transforming growth factor p CTGF-p), which promotes smooth musde differentiation; and bone morphogenetic proteins 2 and 4 (BMP2/4), which promote the diierenti- ation of autonomic neurons and, to a lesser extent, smooth muscle*g. Serial observation of individual clones strongly suggests that, in each case, the growth factor acts to promote the development of one lineage at the expense of otherO~26 (Fig. 3). Thus, the neural crest is one of the few systems in which growth factors have been demonstrated to influence instructively the fate of mufti- potent stem cells. By contrast, in haematopoiesis there is clear evidence that at least some growth factors, such as erythropoietin, act selectivelyz7. This does not mean that growth factors do not exert selective effects on crest development as well: indeed there is evidence that GGF cm also act as a survival factor for Schwann cell

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FIGUIE 3. Growth factors thar promore development of diierent neural crest lineages from mammalian neural crejt stem cells

in u&n Each of the factors indicated is Iiely to work in an instructive, rather than a selective, manner as determined by clonal analysis. (Reproduced with permission from Ref. 19-I

precursors~, and neurotrophins were or&ally identified by their survival promoting effects on crestderived peripheral neurons (reviewed in Ref. 29).

The observation that growth factors can instructively influence the fate of neural crest cells raises additional interesting questions. Is the effect of a given factor primarily positive (i.e. to promote a given fate), negative (i.e. to inhibit alternative fates), or both? How does a neural crest cell integrate the combined influence of opposing signals? Are neural crest ceils equally competent to respond to all signals at the same time, or are there windows of opportunity for the cells to respond to different signals, which change with time? How do these growth-factor-signalling systems interface with other celt-cell signalling systems, such as NOTCH and its li- gandsw, which are known to be expressed by developing neural crest derivatives as welB*?

Sources and requirements for environmental signals u&ting neural crest dewlopment in vivo

Although factors such as GGF, TGF-8 and BMPU4 can influence neural crest cell fate in vitro, it is not certain that they play this role in viva. The evidence is not yet ali in, but most of it is consistent with the in vitro results. All three growth factors are expressed in the appropriate places at appropriate times: neuregulins and their receptors in developing peripheral nerves (where Schwann cells are located)32; TGF-p in the major vessels of the heatt (whose smooth muscle ceils are crest- derivedP; and BMP2/4 in the do& aorta and gut (structures near or within which various classes of autonomic neurons develop) l9*3*. Targeted mutations in the neuregulin gene reduce the number of glial cells associated with peripheral nenes35, while a TGF-p knockout interferes with cardiac development (reviewed in Ref. 36). Unfortunately, embryos homozygous for mutations in BMP2 or BMP4 die too early to assess a requirement for these factors in autonomic neurogenesis (A. Bradley, pers. cormnun.). Tissue-specific knockouts of these li- gands or their receptors will, therefore, be necessary to address this issue.

A number of other growth factors have been revealed, by genetic experiments, to be important in mammalian crest development. Many of these factors are required for proper melanogenesis, reflecting the fact that dominant coat colour mutations are easily detected in mice37. However, some of the same mutations also

affect other neura1 crest lineages that give rise to inter- nal structures, such as the emetic nervous system. For exampie, endotheh 3 and its receptor are required for melanogenesis and enteric neurogenesis (reviewed in Ref. 37). However, this linkage is not always maintained: for e.xample, Steel factor, plateletderived growth factor, and their respective receptors are required for melano- cyte, but not enteric, development (reviewed in Ref. 381, while glialderived neurotrophic factor and its receptor RET are required for enteric neurogenesis, but not melanogenesis (reviewed in Ref. 391. Interestingly, mutations in the human counterparts of some of these genes are associated with various diis, such as piebaldism, agangliogenesis of the bowel and multiple endocrine neoplasia, an inheritd cancer (reviewed in Refs 37, 40). Finally, endotheh 1 and its receptor are required for the development of craniofacial stmctures and the major o&low vessels of the hear@42, which are populated by crest-derived cartilage and smooth muscle, respectively. These in z&a data leave Opt31 the questions of whether these environmental signals act as lineage determinants, survival factors, mitogens, or differentiation signals, and whether they act singly or in combination with other factors. In ujttvexperiments are beginning to address these issue&a.

Transcriitkfactorsirnportantinneuralcrest kagedek&lWon Role of the bHLH transcription fuctor mammalian achaete-scute homologlre 1 (MASHI) in autonomic neunzgenesis

Several transcription factors that are important in neural crest development have been identified, princi- pally using reverse-genetic techniques. Two mammalian homologues of the Dnxopbilu proneural genes achaete- scute, encoding basic-helix-loop-helix (bHLH) transcription factors, were isolated from a cefl line of neural crest origin45. Of these two genes, the mammalian achaete-scute homologue I (Mu&I) is expressed in precursors of all autonomic neurons, but not in those of sensory neurons4‘ (enigmatically, Mash2 is expressed only in the placenta‘?. A targeted mutation in MashI blocks the development of sympathetic, parasympathetic and a subset of enteric neuror&s#@. In vitro analysis of wild-type and Mu&l mutant neural crest ceils has sug- gested that the gene is required for neuronal differentiation, probably after cells have become committed to a neuronal fate%. However, the gene is expressed initially in more primitive cell@, raising the possibility that it has an earlier role not revealed by the null mutation. This idea is supported by recent gain-of-function experiments, which suggest that MASH1 maintains competence for neurogenesis in uncommitted post-migratory neural crest cells74. Thus, MASH1 might play multiple roles at successive stages of autonomic neurogenesis, only one of which is revealed by conventional loss-of-function mutational analysis,

Recent data have shed light on the extracellular signals that induce the synthesis of MASH1 in neural crest cells. In vitro, MASH1 is induced within six hours by BMP2, which, as mentioned earlier, also promotes the differentiation of autonomic neurons (the cell type in which MASH1 function is required)l”. In vivo, MASHl- expressing cells, which are precursors of sympathetic


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neurons, first appear adjacent to the dorsal aorta, which expresses BMP2 (Refs 19, 461. Explants of dorsal aom can induce the synthesis of MASH1 in cultured neural crest cells, and thii induction can be blocked by noggin (A. Groves, N. Shah and DJ. Anderson, unpub- lished), which inhibits the action of BMP2 and BMP4 (Ref. 51). These results suggest that BMP2 and/or BMP4 can induce the production of MASH1 in &I, although, for reasons mentioned earlier, it has nor yet been possible to verify this geneti- cally. Taken together, these data provide one of the first examples of a link between a growth factor and an essential transcription factor in controlling the development of a specific neural crest sublineage.

A subfumi@ of bHLH transcription factors for seh?_wy neurogenesis

Because MASH1 is not synthe- sized in sensory ganglia, it seems

0 Neural crest _

Smooth muscle

Other sensory sublineages Enteric

WUUE 4. Basic-heiix-ioopheiii transcription factors associated with the development of different neural crest sublineages. The sequentia: king of factors within a given lineage indicates sequential expression, not dependent function, although in Xenopus, neumgedn 1 OgnlJ has been shown to activate expression of Xenopus NerlmD(Ref. 52). Genes marked by an asterisk have been shown to be essential for the indicated iieages ill uim by targeted mutagenesis in mouse.

likely that there are other bHLH transcription factors that play a role analogous to that of MASH1 in sensory neurogenesis. Recently, two genes have been isolated that appear to tillill thii expectation: ne~m&~in I (Ref. 52) and neurogenin 2 (also known as Matb4A)y-ji. Both genes are expressed in sensory but not autonomic ganglia, complementary to Mash2 (Fig. 4). In Xenopus embryos, nawcgenin I and a Xenopzrs homoiogue (X-#@r-Z) function as neuronai determination genes, activating expression of the bHLH factor NEUROD and of down- stream markers, such as N-tubuiinsz. In mouse embryos, NEUROD (Ref. 55), and the bHLH factors NSCLl and 2 (Refs 56, 57) are also expressed following the neuro- genins (Refs 52, 54, 581, suggesting that these bHLH proteins function in a cascade in the sensory lineage (Fig. 4). Interestingly, nezlrogetzin 2 is expressed in crest-, otic- and trigeminai-piacodederived cranial xn- sory ganglia, whereas newoge?zin 2 is expressed in those ganglia whose neurons derive from the epibranchiai piacodesj3.5*. These data suggest that these two bHLH factors can control the development of different subclasses of sensory neurons. Targeted mutations in these genes, which are in progress, should test this hypothesis.

Literally dozens of different transcription factors in various gene families have been shown to be expressed in the neural crest or its derivatives i>z vir~. A full listing of these is beyond the scope of this review, so those factors for which essential roles in neural crest development have been demonstrated by genetic experiments are highlighted, focusing on the lineages in which they are required.

Several transcription factors importanr for sensory neurogenesis have been identified. The POLldomain homeoprotein Br&0/3a (renamed Pou4fll) is essential for the differentiation of subsets of sensory neuron@@. In

mutant animals sensory neurons appear to differentiate normally but then die, suggesting that these factors might control, for example, the expression of neurotrophins or their receptors. ISLETI, a founding member of the WM family of homeoproteins, is required for the differentiation or survival of sensory as well as motorneuron@. PAX3, a paired homeodornain transcription factor, is essen- tiai for the development of sensory ganglia as revealed by the Splotch mutation (reviewed in Ref. 621, although whether it is autonomously involved in the development of neurons, glia63, or both, remains to be determined.

Several transcription fdctors have been shown to be essential for different stages in the development of Schwann ceils in viva, including the POUdomain factor SCfP/TSTl/OC%, and the zinc finger protein KROX20 CRefs 64-66; reviewed in Ref. 67). However, these genes are probably expressed too late to function in Schwann cell lineage determination. The microphtbulmia gene encodes a bHLH-Zip protein that is specii%zaliy expressed in meianocyte precursors (Fig. 4) and that is probably a regulator of pigment cell-specific genes (reviewed in Ref. 68). Ho3c genes and retinoic acid receptors are clearly important for the development of mesectoder- mai neural crest derivatives in the hindbrain region, including the branchial arches (reviewed in Ref. 69). Finally, the bHLH proteins eHAND (Refs 70, 71) and dHAND (Ref. 72) are expressed in neural crest-derived smooth muscle ceils (Fig. 4) in the major outdow tracts of the heart, and have been functionally implicated in cardiac development by antisense experiments72.

The analysis of neural crest development has entered a new era, as the combination of reverse-genetic experiments and in tfitm studies continues to identify impor- taut genes and to establish their cellular mechanisms of action. Furthermore, the recent completion of a iarge- scale saturation mutagenesis experiment in zebrafish

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(reviewed in Ref. 73) promises a cornucopia of new genes that are important in crest devetopment that could not have been identified by any other means. At the same time, ongoing cellular experiments will establish the partem of lineage restrictions that occur and should identify extracellular signals that influence the development of different crest sublineages. The ability to add or to delete genes from neural crest cells and then to chaI- lenge them, by transplantation in c4:o or exposure to defined signals in vitro, should help to shed new light on the important issue of when and how these multipotent cells become committed to particular fates.

Aclmowkdgeme~ts work described from the author-s laboratory was

supported by the NIH, Muscular Dystrophy Association and the Howard Hughes Medical institute. I thank mem- bers of my laboratory for helpful discussions, and Nirao Shah for the preparation of Fig. 1.

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cellular and molecular biology of neural crest cell lineage determination

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