Hedgehog and Patched in Neural Development and Disease
Authors: Lisa V Goodrich, Matthew P Scott
Journal: Neuron (1998)

The vertebrate central nervous system is organized into functional units dedicated to specific tasks such as the detection of form and of movement. Understanding the embryogenesis of these patterns is a daunting task, but it has been aided greatly by genetic studies in model organisms such as the fruit fly Drosophila. The strength of this approach is exemplified by the Hedgehog (Hh) signaling system, initially identified in flies and subsequently found to play an essential role in human neural development and disease. Misregulation of Hh signaling in humans is associated with mental retardation and gross neural tube defects such as spina bifida, which is a malformation of the spinal column, and holoprosencephaly, a loss of midline structures in the brain and face (8Belloni E. Muenke M. Roessler E. Traverso G. Siegel-Bartelt J. Frumkin A. Mitchell H.F. Donis-Keller H. Helms C. Hing A. et al.Identification of Sonic Hedgehog as a candidate gene responsible for holoprosencephaly.Nat. 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In adults, the Hh pathway is essential for restraining growth in the nervous system and other tissues; mutations in pathway components lead to a variety of tumors, including basal cell carcinoma, the most common human cancer, and medulloblastoma, a childhood brain tumor (49Gailani M.R. Stahle-Backdahl M. Leffell D.J. Glynn M. Zaphiropoulos P.G. Pressman C. Unden A.B. Dean M. Brash D.E. Bale A.E. Toftgard R. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas.Nat. Genet. 1996; 14: 78-81Crossref PubMed Scopus (473) Google Scholar, 57Hahn H. Wicking C. Zaphiropoulous P.G. Gailani M.R. Shanley S. Chidambaram A. Vorechovsky I. Holmberg E. Unden A.B. Gillies S. et al.Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.Cell. 1996; 85 (b): 841-851Abstract Full Text Full Text PDF PubMed Scopus (1187) Google Scholar, 86Johnson R.L. Rothman A.L. Xie J. Goodrich L.V. Bare J.W. Bonifas J.M. Quinn A.G. Myers R.M. Cox D.R. Epstein Jr., E. Scott M.P. Human homolog of patched, a candidate gene for the basal cell nevus syndrome.Science. 1996; 272: 1668-1671Crossref PubMed Google Scholar, 139Oro A.E. Higgins K.M. Hu Z. Bonifas J.M. Epstein E.H. Scott M.P. Basal cell carcinomas in mice overexpressing Sonic Hedgehog.Science. 1997; 276: 817-821Crossref PubMed Scopus (476) Google Scholar, 148Pietsch T. Waha A. Koch A. Kraus J. Albrecht S. Tonn J. Sorensen N. Berthold F. Henk B. Schmandt N. et al.Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched.Cancer Res. 1997; 57: 2085-2088PubMed Google Scholar, 159Raffel C. Jenkins R.B. Frederick L. Hebrink D. Alderete B. Fults D.W. James C.D. Sporadic medulloblastomas contain PTCH mutations.Cancer Res. 1997; 57: 842-845PubMed Google Scholar, 195Unden A.B. Zaphiropoulos P.G. Bruce K. Toftgard R. Stahle-Backdahl M. Human patched (PTCH) mRNA is overexpressed consistently in tumor cells of both familial and sporadic basal cell carcinoma.Cancer Res. 1997; 57: 2336-2340PubMed Google Scholar, 204Wolter M. Reifenberger J. Sommer C. Ruzicka T. Reifenberger G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.Cancer Res. 1997; 57: 2581-2585PubMed Google Scholar, 205Xie J. Johnson R.L. Zhang X. Bare J.W. Waldman F.M. Cogen P.H. Menon A.G. Warren R.S. Chen L.C. Scott M.P. Epstein Jr., E. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors.Cancer Res. 1997; 57: 2369-2372PubMed Google Scholar). Understanding Hh signaling may lead to improved treatments for these human disorders. Although "the Hh pathway" is now diagrammed in many textbooks, many questions remain, not least of which is how the Hh signal is sent and received. In this review, we focus on what has been learned about Hh signaling in the nervous system, how regulation of cell fate and cell division are interwoven, and what we now know about the intracellular steps in Hh signal transduction. We begin with an introduction to two key members of the pathway: Hh itself and its proposed receptor, Patched (Ptc). As was initially described in the Drosophila embryonic epidermis, the segment polarity genes hh and ptc oppose each other's activity (80Ingham P.W. Taylor A.M. Nakano Y. Role of the Drosophila patched gene in positional signaling.Nature. 1991; 353: 184-187Crossref PubMed Scopus (238) Google Scholar). This mutual restraint leads to precisely coordinated patterns of gene transcription, differentiation, and growth. hh encodes a secreted protein (99Lee J.J. von Kessler D.P. Parks S. Beachy P.A. Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog.Cell. 1992; 71: 33-50Abstract Full Text PDF PubMed Scopus (331) Google Scholar, 125Mohler J. Vani K. Molecular organization and embryonic expression of the hedgehog gene involved in cell-cell communication in segmental patterning of Drosophila.Development. 1992; 115: 8957-8971Google Scholar, 185Tabata T. Eaton S. Kornberg T.B. The Drosophila hedgehog gene is expressed specifically in posterior compartment cells and is a target of engrailed regulation.Genes Dev. 1992; 6: 2635-2645Crossref PubMed Google Scholar) that regulates cell fate determination and, in some tissues, induces proliferation. Ptc is a transmembrane protein (70Hooper J.E. Scott M.P. The Drosophila patched gene encodes a putative membrane protein required for segmental patterning.Cell. 1989; 59: 751-765Abstract Full Text PDF PubMed Google Scholar, 130Nakano Y. Guerrero I. Hidalgo A. Taylor A. Whittle J.R.S. Ingham P.W. A protein with several possible membrane-spanning domains encoded by the Drosophila segment polarity gene patched.Nature. 1989; 341: 508-513Crossref PubMed Google Scholar) that dictates alternative developmental decisions or inhibits growth unless opposed by Hh activity. For example, in ptc mutant fly embryos, the central pattern elements of the ventral epidermis are deleted and replaced with mirror-image duplications of the segment borders (134Nüsslein-Volhard C. Wieschaus E. Mutations affecting segment number and polarity in Drosophila.Nature. 1980; 287: 795-801Crossref PubMed Google Scholar, 120Martinez Arias A. Baker N.E. Ingham P.W. Role of segment polarity genes in the definition and maintenance of cell states in the Drosophila embryo.Development. 1988; 103: 157-170PubMed Google Scholar); nearly the same phenotype is seen when hh is ubiquitously expressed (79Ingham P.W. Hidalgo A. Regulation of wingless transcription in the Drosophila embryo.Development. 1993; 117: 283-291PubMed Google Scholar). Either loss of Ptc or too much Hh leads to ectopic transcription of the wingless (wg) gene, which encodes a secreted Wnt-class signal that controls cell fates. Thus, hh normally maintains wg transcription in a limited region, and ptc normally represses wg outside that region. Despite the gross patterning defects observed in ptc mutant embryos, no change in cell division frequency or pattern has been noted (120Martinez Arias A. Baker N.E. Ingham P.W. Role of segment polarity genes in the definition and maintenance of cell states in the Drosophila embryo.Development. 1988; 103: 157-170PubMed Google Scholar). In contrast, during imaginal disc development, Hh signaling strongly affects both cell fate and growth. Cells that lack Ptc or are exposed to high levels of Hh assume fates of cells usually found in the central wing region (Figure 1) (147Phillips R.G. Roberts I.J.H. Ingham P.W. Whittle J.R.S. The Drosophila segment polarity gene patched is involved in a position-signaling mechanism in imaginal discs.Development. 1990; 110: 105-114PubMed Google Scholar, 78Ingham P.W. Fietz M.J. Quantitative effects of hedgehog and decapentaplegic activity on the patterning of the Drosophila wing.Curr. Biol. 1995; 5: 432-440Abstract Full Text Full Text PDF PubMed Google Scholar). In addition, either ectopic expression of Hh or loss of Ptc function causes dramatic mirror-image duplications or triplications in the legs and wings (147Phillips R.G. Roberts I.J.H. Ingham P.W. Whittle J.R.S. The Drosophila segment polarity gene patched is involved in a position-signaling mechanism in imaginal discs.Development. 1990; 110: 105-114PubMed Google Scholar, 6Basler K. Struhl G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein.Nature. 1994; 368: 208-214Crossref PubMed Scopus (559) Google Scholar). In contrast, excess Ptc inhibits growth, leading to small wings (85Johnson R.L. Grenier J.K. Scott M.P. patched overexpression alters wing disc size and pattern transcriptional and post-transcriptional effects on hedgehog targets.Development. 1995; 121: 4161-4170PubMed Google Scholar). Some of these effects are due to Hh induction of decapentaplegic (dpp), a TGFβ-class signal, in a stripe along the border between the anterior and posterior compartments (Figure 1) (6Basler K. Struhl G. Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein.Nature. 1994; 368: 208-214Crossref PubMed Scopus (559) Google Scholar, 184Tabata T. Kornberg T. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs.Cell. 1994; 76: 89-102Abstract Full Text PDF PubMed Scopus (396) Google Scholar). Again, Ptc acts in opposition to Hh and inhibits dpp transcription (20Capdevila J. Estrada M.P. Sánchez-Herrero E. Guerrero I. The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development.EMBO J. 1994; 13 (b): 71-82Crossref PubMed Scopus (176) Google Scholar, 85Johnson R.L. Grenier J.K. Scott M.P. patched overexpression alters wing disc size and pattern transcriptional and post-transcriptional effects on hedgehog targets.Development. 1995; 121: 4161-4170PubMed Google Scholar). Dpp appears to be responsible for much of Hh's long-range activity in discs (18Capdevila J. Guerrero I. Targeted expression of the signaling molecule decapentaplegic induces pattern duplications and growth alterations in Drosophila wings.EMBO J. 1994; 13: 4459-4468Crossref PubMed Google Scholar, 78Ingham P.W. Fietz M.J. Quantitative effects of hedgehog and decapentaplegic activity on the patterning of the Drosophila wing.Curr. Biol. 1995; 5: 432-440Abstract Full Text Full Text PDF PubMed Google Scholar). Both Dpp and Wg act as long-range signals and can cause extensive pattern rearrangements when misexpressed (131Nellen D. Burke R. Struhl G. Basler K. Direct and long-range action of a dpp morphogen gradient.Cell. 1996; 85: 357-368Abstract Full Text Full Text PDF PubMed Scopus (652) Google Scholar, 210Zecca M. Basler K. Struhl G. Direct and long-range action of a wingless morphogen gradient.Cell. 1996; 87: 833-844Abstract Full Text Full Text PDF PubMed Scopus (469) Google Scholar). Normal development therefore depends on the ability of Hh and Ptc to restrict production of secondary signals to the right places. The mutual antagonism between Hh and Ptc also controls the transcription of ptc itself (80Ingham P.W. Taylor A.M. Nakano Y. Role of the Drosophila patched gene in positional signaling.Nature. 1991; 353: 184-187Crossref PubMed Scopus (238) Google Scholar). In many tissues, cells that receive Hh signal increase transcription of ptc (Figure 2). Out of range of a Hh source, Ptc represses its own transcription and therefore ptc RNA is present at low levels. ptc expression remains at low levels in hh mutants or when Ptc is overexpressed (68Hidalgo A. Ingham P.W. Cell patterning in the Drosophila segment spatial regulation of the segment polarity gene patched.Development. 1990; 110: 291-301PubMed Google Scholar, 80Ingham P.W. Taylor A.M. Nakano Y. Role of the Drosophila patched gene in positional signaling.Nature. 1991; 353: 184-187Crossref PubMed Scopus (238) Google Scholar, 172Sampedro J. Guerrero I. Unrestricted expression of the Drosophila gene patched allows a normal segment polarity.Nature. 1991; 353: 187-190Crossref PubMed Scopus (19) Google Scholar, 20Capdevila J. Estrada M.P. Sánchez-Herrero E. Guerrero I. The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development.EMBO J. 1994; 13 (b): 71-82Crossref PubMed Scopus (176) Google Scholar, 85Johnson R.L. Grenier J.K. Scott M.P. patched overexpression alters wing disc size and pattern transcriptional and post-transcriptional effects on hedgehog targets.Development. 1995; 121: 4161-4170PubMed Google Scholar). Conversely, ptc transcription is elevated in ptc mutant embryos and discs (68Hidalgo A. Ingham P.W. Cell patterning in the Drosophila segment spatial regulation of the segment polarity gene patched.Development. 1990; 110: 291-301PubMed Google Scholar, 20Capdevila J. Estrada M.P. Sánchez-Herrero E. Guerrero I. The Drosophila segment polarity gene patched interacts with decapentaplegic in wing development.EMBO J. 1994; 13 (b): 71-82Crossref PubMed Scopus (176) Google Scholar). This relationship is evolutionarily conserved in vertebrates, where three different Hh proteins—Sonic hedgehog (Shh), Desert hedgehog (Dhh), and Indian hedgehog (Ihh)—each induce high-level ptc transcription (11Bitgood M.J. Shen L. McMahon A.P. Sertoli cell signaling by Desert hedgehog regulates the male germline.Curr. 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Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein.Science. 1996; 273: 613-622Crossref PubMed Google Scholar). In addition, Ptc is both necessary and sufficient for its own transcriptional repression in most murine tissues (54Goodrich L.V. Milenkovic L. Higgins K.M. Scott M.P. Altered neural cell fates and medulloblastoma in mouse patched mutants.Science. 1997; 277: 1109-1113Crossref PubMed Scopus (949) Google Scholar; L. V. G. and M. P. S., unpublished data). Thus, in both flies and mice, ptc transcription is an excellent indicator of Hh and Ptc activity (Figure 2). Studies of the Hh pathway in vertebrates have pushed forward our understanding of a number of developmental processes, especially in the nervous system. A striking feature of vertebrate CNS organization is the spatial organization of neurons according to their functions. For example, sensory neurons are in the dorsal horn of the spinal cord and motor neurons are ventral (reviewed by 188Tanabe Y. Jessell T.M. Diversity and pattern in the developing spinal cord.Science. 1996; 274: 1115-1123Crossref PubMed Scopus (564) Google Scholar). How does this pattern arise during development? Embryological manipulations and molecular analysis have brought developmental neurobiologists much closer to an answer to this classic question. The dorsal–ventral polarization is apparently established in the developing neural tube by signals from the overlying surface ectoderm and from an underlying rod of axial mesoderm, the notochord (Figure 3). The dorsal-most and ventral-most cells of the neural tube—the roof plate and floor plate, respectively—acquire the organizing properties of the ectoderm and notochord and subsequently help pattern the rest of the neural tube. The roof plate and floor plate consist of specialized, nonneuronal cells that are histologically distinct from the neuroepithelium. While dorsal cell types can be induced by bone morphogenetic protein (BMP)–like signals from the ectoderm and roof plate (106Liem Jr., K. Tremml G. Roelink H. Jessell T.M. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm.Cell. 1995; 82: 969-979Abstract Full Text PDF PubMed Scopus (746) Google Scholar, 107Liem K.F. Tremml G. Jessell T.M. A role for the roof plate and its resident TGFβ-related proteins in neuronal patterning in the dorsal spinal cord.Cell. 1997; 91: 127-138Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar), ventral cell types can be induced by the Hh family member Sonic hedgehog (Shh) produced by the notochord and floor plate. Much evidence supports the hypothesis that Shh secreted from the axial mesoderm induces formation of the floor plate by preventing Ptc function. Both Shh and ptc are expressed at the right time and place, Shh in the notochord (35Echelard Y. Epstein D.J. St.-Jacques B. Shen L. Mohler J. McMahon J.A. McMahon A.P. Sonic hedgehog, a member of a family of putative secreted signaling molecules, is implicated in the regulation of CNS polarity.Cell. 1993; 75: 1417-1430Abstract Full Text PDF PubMed Scopus (1259) Google Scholar) and ptc in the presumptive floor plate though not in the differentiated floor plate (Figure 2) (53Goodrich L.V. Johnson R.L. Milenkovic L. McMahon J. Scott M.P. Conservation of the hedgehog/patched signaling pathway from flies to mice induction of a mouse patched gene by hedgehog.Genes Dev. 1996; 10: 301-312Crossref PubMed Google Scholar). Since Shh induces ptc transcription (53Goodrich L.V. Johnson R.L. Milenkovic L. McMahon J. Scott M.P. Conservation of the hedgehog/patched signaling pathway from flies to mice induction of a mouse patched gene by hedgehog.Genes Dev. 1996; 10: 301-312Crossref PubMed Google Scholar, 117Marigo V. Scott M.P. Johnson R.L. Goodrich L. Tabin C.J. Conservation in hedgehog signaling Sonic hedgehog controls the expression of a chicken patched homolog in the developing limb.Development. 1996; 122 (c): 1225-1233Crossref PubMed Google Scholar), a Shh signal from the mesoderm is apparently received by cells in the ventral neural tube. Moreover, Shh has floor plate–inducing activity: ectopic Shh induces neural cells to assume both molecular and histological properties of the floor plate (reviewed by 42Ericson J. Briscoe J. Rashbass P. van Heyningen V. Jessell T.M. Graded Sonic hedgehog signaling and the specification of cell fate in the ventral neural tube.Cold Spring Harbor Symp. Quant. Biol. 1997; 52 (b): 451-466Google Scholar). High concentrations of Shh are needed for this activity, consistent with the fact that notochord induction of floor plate is contact dependent (150Placzek M. Tessier-Lavigne M. Yamada T. Jessell T. Dodd J. Mesodermal control of neural cell identity floor plate induction by the notochord.Science. 1990; 250: 985-988Crossref PubMed Google Scholar, 151Placzek M. Jessell T.M. Dodd J. Induction of floor plate differentiation by contact-dependent, homeogenetic signals.Development. 1993; 117: 205-218PubMed Google Scholar, 164Roelink H. Augsburger A. Heemskerk J. Korzh V. Norlin S. Ruiz i Altaba A. Tanabe Y. Placzek M. Edlund T. Jessell T.M. Dodd J. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord.Cell. 1994; 76: 761-775Abstract Full Text PDF PubMed Scopus (554) Google Scholar, 165Roelink H. Porter J.A. Chiang C. Tanabe Y. Chang D.T. Beachy P.A. Jessell T.M. Floor plate and motor neuron induction by different concentrations of the amino-terminal cleavage product of Sonic hedgehog autoproteolysis.Cell. 1995; 81: 445-455Abstract Full Text PDF PubMed Google Scholar). Shh is also necessary for floor plate formation; the floor plate fails to develop in mice lacking Shh function and when Shh activity is inhibited by function-blocking antibodies (25Chiang C. Litingtung Y. Lee E. Young K.E. Corden J.L. Westphal H. Beachy P.A. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.Nature. 1996; 383: 407-413Crossref PubMed Scopus (1866) Google Scholar, 40Ericson J. Morton S. Kawakami A. Roelink H. Jessell T.M. Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity.Cell. 1996; 87: 661-673Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar). As in flies, mutations in ptc have the opposite effect: floor plate–like cells develop throughout much of the neuroepithelium of mouse ptc mutants (54Goodrich L.V. Milenkovic L. Higgins K.M. Scott M.P. Altered neural cell fates and medulloblastoma in mouse patched mutants.Science. 1997; 277: 1109-1113Crossref PubMed Scopus (949) Google Scholar). Transplant experiments and mutant phenotypes indicate that Shh inactivation of Ptc is important for floor plate determination, but they do not settle the question of when the Shh pathway works during normal development. Does Shh signaling normally occur between the notochord and ventral neural tube, or does Shh direct floor plate development earlier, during gastrulation? The node is a morphologically distinct region anterior to the primitive streak of the gastrula and can induce formation of an additional body axis when transplanted to an ectopic location (reviewed by 187Tam P.P.L. Steiner K.A. Zhou S.X. Quinlan G.A. Lineage and functional analyses of the mouse organizer.Cold Spring Harbor Symp. Quant. Biol. 1997; 52: 135-144Google Scholar). It therefore has the properties of the Spemann organizer first described in Xenopus. Several observations support the idea that Shh acts first in the node and then in the neural tube. First, unlike the rest of the neural tube, the floor plate, like the notochord, is derived in part from the node and not from the ectoderm (177Selleck M.A. Stern C.D. Fate mapping and cell lineage analysis of Hensen's node in the chick embryo.Development. 1991; 112: 615-626PubMed Google Scholar, 22Catala M. Teillet M.A. Robertis E.M.D. Douarin N.L.L. A spinal cord fate map in the avian embryo while regressing, Hensen's node lays down the notochord and floor plate, thus joining the spinal cord lateral walls.Development. 1996; 122: 2599-2610PubMed Google Scholar). Thus, floor plate and notochord precursor cells are closely associated in the gastrula. Second, both Shh and ptc are expressed in the node (35Echelard Y. Epstein D.J. St.-Jacques B. Shen L. Mohler J. McMahon J.A. McMahon A.P. Sonic hedgehog, a member of a family of putative secreted signaling molecules, is implicated in the regulation of CNS polarity.Cell. 1993; 75: 1417-1430Abstract Full Text PDF PubMed Scopus (1259) Google Scholar, 162Riddle R.D. Johnson R.L. Laufer E. Tabin C. Sonic hedgehog mediates the polarizing activity of the ZPA.Cell. 1993; 75: 1401-1416Abstract Full Text PDF PubMed Scopus (1411) Google Scholar, 53Goodrich L.V. Johnson R.L. Milenkovic L. McMahon J. Scott M.P. Conservation of the hedgehog/patched signaling pathway from flies to mice induction of a mouse patched gene by hedgehog.Genes Dev. 1996; 10: 301-312Crossref PubMed Google Scholar, 117Marigo V. Scott M.P. Johnson R.L. Goodrich L. Tabin C.J. Conservation in hedgehog signaling Sonic hedgehog controls the expression of a chicken patched homolog in the developing limb.Development. 1996; 122 (c): 1225-1233Crossref PubMed Google Scholar). Third, a differentiated notochord does not appear to be required for floor plate formation, since a Shh-expressing floor plate develops in no tail zebrafish mutants, which have notochord precursor cells but no notochord (61Halpern M.E. Ho R.K. Walker C. Kimmel C.B. Induction of muscle pioneers and floor plate is distinguished by the zebrafish no tail mutation.Cell. 1993; 75: 99-111Abstract Full Text PDF PubMed Google Scholar, 135Odenthal J. Haffter P. Vogelsang E. Brand M. van Eeden F.J. Furutani-Seiki M. Granato M. Hammerschmidt M. Heisenberg C.P. Jiang Y.J. et al.Mutations affecting the formation of the notochord in the zebrafish, Danio rerio.Development. 1996; 123: 103-115PubMed Google Scholar). Taken together, the results suggest that floor plate induction by the axial mesoderm might commence within the node, not after the notochord and neural tube are fully formed. Another unresolved issue is whether the Shh signal is instructive, permissive, or both. In the fly epidermis, Hh signaling does not initiate the wg expression pattern but instead maintains preexisting wg transcription (79Ingham P.W. Hidalgo A. Regulation of wingless transcription in the Drosophila embryo.Development. 1993; 117: 283-291PubMed Google Scholar). By analogy, in the vertebrate nervous system, preexisting floor plate precursors could be preserved, or their growth stimulated, by a Shh signal. Indeed, Shh can act as a trophic factor for some midbrain progenitors (123Miao N. Wang M. Ott J.A. D'Alessandro J.S. Woolf T.M. Bumcrot D.A. Mahanthappa N.K. Pang K. Sonic hedgehog promotes the survival of specific CNS neuron populations and protects these cells from toxic insult in vitro.J. 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Altered neural cell fates and medulloblastoma in mouse patched mutants.Science. 1997; 277: 1109-1113Crossref PubMed Scopus (949) Google Scholar). In support of an instructive role, different concentrations of Shh can direct different cell fates in the ventral neural tube (40Ericson J. Morton S. Kawakami A. Roelink H. Jessell T.M. Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity.Cell. 1996; 87: 661-673Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar, 41Ericson J. Rashbass P. Schedl A. Brenner-Morton S. Kawakami A. van Heyningen V. Jessell T.M. Briscoe J. Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.Cell. 1997; 90 (a): 169-180Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar), and ectopic Shh can reprogram dorsal cells to assume a floor plate identity. Thus, in different biological contexts, Shh may control cell fate, cell survival, or cell growth. Since proliferation of a committed set of precursors also generates cell fate changes, defining the primary role of Shh is challenging. In addition to its proposed role in floor plate development, Shh signaling also appears to control the fate and position of motor neurons and interneurons in the ventral spinal cord (Figure 3). Shh is proposed to ventralize neural tube progenitors by repressing expression of dorsal determinants such as Pax3 (40Ericson J. Morton S. Kawakami A. Roelink H. Jessell T.M. Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity.Cell. 1996; 87: 661-673Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar, 41Ericson J. Rashbass P. Schedl A. Brenner-Morton S. Kawakami A. van Heyningen V. Jessell T.M. Briscoe J. Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.Cell. 1997; 90 (a): 169-180Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). This requires very low concentrations of Shh, in keeping with the repression of dorsal markers within ten cell diameters of the floor plate (40Ericson J. Morton S. Kawakami A. Roelink H. Jessell T.M. Two critical periods of sonic hedgehog signaling required for the specification of motor neuron identity.Cell. 1996; 87: 661-673Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar). In vitro experiments suggest that 2-fold changes in the concentration of Shh subsequently induce specific types of cells at different dorsal–ventral positions in the spinal cord (41Ericson J. Rashbass P. Schedl A. Brenner-Morton S. Kawakami A. van Heyningen V. Jessell T.M. Briscoe J. Pax6 controls progenitor cell identity and neuronal fate in response to graded Shh signaling.Cell. 1997; 90 (a): 169-180Abstract Full Text Full Text PDF PubMed Scopus (643) Google