Review Articles
You have full text access to this OnlineOpen article
Brain as a paradigm of organ growth: Hedgehog–Gli signaling in neural stem cells and brain tumors
Article first published online: 22 JUL 2005
DOI: 10.1002/neu.20160
Copyright © 2005 Wiley Periodicals, Inc.
Issue

Journal of Neurobiology
Special Issue: Unexpected Roles for Morphogens in the Development and Regeneration of the CNS
Volume 64, Issue 4, pages 476–490, 15 September 2005
Additional Information
How to Cite
Stecca, B. and Ruiz i Altaba, A. (2005), Brain as a paradigm of organ growth: Hedgehog–Gli signaling in neural stem cells and brain tumors. J. Neurobiol., 64: 476–490. doi: 10.1002/neu.20160
Publication History
- Issue published online: 22 JUL 2005
- Article first published online: 22 JUL 2005
- Manuscript Accepted: 3 JAN 2005
- Manuscript Received: 22 DEC 2004
Funded by
- NIH-NINDS
- NIH-NCI
- HFSP
- Pew Trusts
- Hirschl and Jeantet Foundations
- Parkinson's Foundation, USA
REFERENCES
- , , , , . 2003. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100: 3983–3988.
- , . 1997. Development of the cerebellar system in relation to its evolution, structure, and function. New York: CRC Press.
- , , . 2001. A unified hypothesis on the lineage of neural stem cells. Nat Rev Neurosci 2: 287–293.
- , . 2004. For the long run: maintaining germinal niches in the adult brain. Neuron 41: 683–686.
- , , , , , , . 1999. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 5: 1285–1291.
- , , , . 2000. Expression of the vertebrate Gli proteins in Drosophila reveals a distribution of activator and repressor activities. Development 127: 4293–4301.
- , . 2001. Gli1 can rescue the in vivo function of Gli2. Development 128: 5161–5172.
- , , , , . 2002. Gli2, but not Gli1, is required for initial Shh signaling and ectopic activation of the Shh pathway. Development 129: 4753–4761.
- , , . 2004. All mouse ventral spinal cord patterning by hedgehog is Gli dependent and involves an activator function of Gli3. Dev Cell 6: 103–115.
- , . 1991. Neocortical development. New York: Raven Press.
- , , , , , , , , , , , , , , , . 1996. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nat Genet 14: 353–356.
- , , , , , , , , , , . 2002. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297: 1559–1561.
- , , , , , , , , , , . 2003. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425: 846–851.
- , . 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3: 730–737.
- , , . 1998. Gli/Zic factors pattern the neural plate by defining domains of cell differentiation. Nature 393: 579–583.
- , , , . 2002. Inhibition of Hedgehog signal by direct binding of cyclopamine to Smoothened. Genes Dev 16: 2743–2748.
- , , , , . 2002. Small molecule modulation of smoothened activity. Proc Natl Acad Sci USA 99: 14071–14076.
- , , , , , . 2004. Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh. Development 131: 2339–2347.
- , , , , , , . 1996. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383: 407–413.
- , , , , , , , , , , , , , . 1999. Essential role for oncogenic Ras in tumour maintenance. Nature 400: 468–472.
- , , , . 1998. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280: 1603–1607.
- , . 1999. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126: 3089–3100.
- , , , , . 1997. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 389: 876–881.
- , , , , , , , . 2001. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 128: 5201–5212.
- , , , , , . 1999. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J Biol Chem 274: 8143–8152.
- , , , , , , , , , , , , , , . 2004. REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci U S A 101: 10833–10838.
- , , , , , , , , . 1999. Mouse suppressor of fused is a negative regulator of sonic hedgehog signaling and alters the subcellular distribution of Gli1. Curr Biol 9: 1119–1122.
- , , , , , , . 1998. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 125: 2533–2543.
- , , , , . 1999. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97: 703–716.
- , , , , . 2002. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36: 1021–1034.
- , , , , , , . 1993. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75: 1417–1430.
- , , , , . 1996. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87: 661–673.
- , , , , . 1992. Early stages of motor neuron differentiation revealed by expression of homeobox gene Islet-1. Science 256: 1555–1560.
- , . 1999. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 4: 199–207.
- , , , , , , , , . 2001. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 15: 3249–3262.
- , , , , , , , , , , , . 2002. Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol 1: 10.
- . 2000. Mammalian neural stem cells. Science 287: 1433–1438.
- , , , , , , , , , . 2004. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64: 7011–7021.
- , , . 1991. Cerebellar granule cell neurogenesis is regulated by cell-cell interactions in vitro. Neuron 6: 705–715.
- , , , . 1997. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277: 1109–1113.
- , . 1998. Hedgehog and patched in neural development and disease. Neuron 21: 1243–1257.
- . 1995. Nevoid basal cell carcinoma syndrome. Dermatol Clin 13: 113–125.
- , , , , , , . 2000. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nat Genet 24: 216–217.
- , , , , , , , . 2003. The magnitude of hedgehog signaling activity defines skin tumor phonotype. EMBO J 22: 2741–2751.
- , , . 2002. Life is a journey: a genetic look at neocortical development. Nat Rev Genet 3: 342–355.
- , , , , , , , , , , , , , , , , , , , , . 1996. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85: 841–851.
- , , , , , . 1998. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med 4: 619–622.
- , , , , , , . 2003. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100: 15178–15183.
- , . 2005. Communicating with Hedgehogs. Nat Rev Mol Cell Biol 6: 306–317.
- , , , , , , . 1995. Induction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron 15: 35–44.
- , , , , , , . 1997. Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron 19: 15–26.
- , , , , , . 2002. Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39: 193–206.
- , . 1976. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci U S A 73: 549–553.
- , , , . 1998. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 125: 3553–3562.
- . 2000. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat Rev Genet 1: 20–29.
- , , , , , , , , , , . 1996. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272: 1668–1671.
- , , , , , , , , . 2004. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431: 707–712.
- , , , , , , . 2003. Genetic analysis of zebrafish gli1 and gli2 reveals divergent requirements for gli genes in vertebrate development. Development 130: 1549–1564.
- . 1970. Teratogenic compounds of Veratrum californicum (Durand) X. Cyclopia in rabbits produced by cyclopamine. Teratology 3: 175–180.
- , . 1989. Oral, osmotic minipump, and intramuscular administration to sheep of the Veratrum alkaloid cyclopamine. Proc Soc Exp Biol Med 192: 153–156.
- , , , , , , , . 1987. Identification of an amplified, highly expressed gene in a human glioma. Science 236: 70–73.
- , , , , , , . 1999. Mammalian suppressor of fused modulates nuclear-cytoplasmic shuttling of Gli1. Nat Cell Biol 1: 312–319.
- , , . 1993. A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75: 1431–1444.
- , , , , , , , . 2004. Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 64: 6071–6074.
- , , , . 2003. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6: 21–27.
- , , , , , , , , , . 1994. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645–648.
- , , , . 1997. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124: 2537–2352.
- , , , . 1992. Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell 71: 33–50.
- , , , , . 2004. Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development 131: 3593–3604.
- , , , , . 2004. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol 270: 393–410.
- , , , , , . 2000. Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28: 713–726.
- , 2000. Specification of ventral neuron types is mediated by an antagonistic interaction between Shh and Gli3. Nat Neurosci 3: 979–985.
- , , , , , , , , . 2000. Sonic hedgehog-regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron 25: 317–329.
- , , , , , , , , , , , , . 2003. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39: 937–950.
- , , , , , , , . 2002. Regulation of Gli1 transcriptional activity in the nucleus by Dyrk1. J Biol Chem 277: 35156–35161.
- , , , . 1995. Requirement of 19K form of Sonic hedgehog for induction of distinct ventral cell types in CNS explants. Nature 375: 322–325.
- , . 1975. Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro. Proc Natl Acad Sci U S A. 72: 1441–1445.
- , , , , . 1998. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development 125: 2759–2770.
- , , , , , , . 1990. Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest 86: 131–140.
- , , , , , , , . 1997. Sonic hedgehog promotes the survival of specific CNS neuron populations and protects these cells from toxic insult in vitro. J Neurosci 17: 5891–5899.
- , . 1975. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci U S A. 72: 3585–3589.
- , , , , , , , , , , , . 1997. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 124: 113–123.
- . 1988. Requirements for hedgehod, a segmental polarity gene, in patterning larval and adult cuticle of Drosophila. Genetics 120: 1061–1072.
- , . 2001. Mechanisms of cerebral cortical patterning in mice and humans. Nat Neurosci 4: 1199–1206.
- , . 2004. Disguising adult neural stem cells. Curr Opin Neurobiol 14: 125–131.
- , , , , , . 2003. Differential requirement for Gli2 and Gli3 in ventral neural cell fate specification. Dev Biol 259: 150–161.
- , , , . 2005. Development. In press.
- , , , , , , . 2000. Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1. Proc Natl Acad Sci U S A 97: 3438–3443.
- , . 1980. Mutations affecting segment number and polarity in Drosophila. Nature 287: 795–801.
- , , , . 1999. Sonic hedgehog signaling is required during the appearance of spinal cord oligodendrocyte precursors. Development 126: 2419–2429.
- , , , , , . 1997. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276: 817–821.
- , . 2002. The control of neural stem cells by morphogenic signals. Curr Opin Genet Dev 12: 478–487.
- , . 2004. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex. Development 131: 337–345.
- , , , , , , , , , . 2005. Sonic hedgehog signaling regulates the behavior of stem cells and early precursors in the postnatal and adult brain. Development 132: 335–344.
- , , , . 1975. Fate of teratocarcinoma cells injected into early mouse embryos. Nature 258: 70–73.
- , , . 2003. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3: 895–902.
- , , , , , , , . 2000. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127: 1593–1605.
- , . 2003. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 3: 903–911.
- , , , . 1999. Vertebrate homologs of Drosophila suppressor of fused interact with the gli family of transcriptional regulators. Dev Biol 212: 323–336.
- , , , , . 1999. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol Cell 3: 565–577.
- , , , , , , , , , , , , . 2002. Long-acting forms of Sonic hedgehog with improved pharmacokinetic and pharmacodynamic properties are efficacious in a nerve injury model. J Pharm Sci 91: 371–387.
- , , , , , , , . 2002. Dorsal-ventral patterning of the spinal cord requires Gli3 transcriptional repressor activity. Genes Dev 16: 2865–2578.
- , , , , , , , , , , , , , , , . 1997. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res 57: 2085–2088.
- , , , , , , , . 1996. Induction of oligodendrocyte progenitors in the trunk neural tube by ventralizing signals: effects of notochord and floor plate grafts, and of sonic hedgehog. Mech Dev 60: 13–32.
- , , , , , , . 1996. Determination of neuroepithelial cell fate: induction of the oligodendrocyte lineage by ventral midline cells and sonic hedgehog. Dev Biol 177: 30–42.
- , , , , , , . 1997. Sporadic medulloblastomas contain PTCH mutations. Cancer Res 57: 842–845.
- , , , , , , . 1998. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 58: 1798–1803.
- , , , , . 2000. Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet 26: 109–113.
- , , , . 2001. Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.
- , . 1996. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175: 1–13.
- , , , , . 1988. A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell 53: 309–19.
- , , , . 1993. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75: 1401–1416.
- , , , , , , , , , , et al. 1994. Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76: 761–775.
- , , , , , , , . 1996. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14: 357–360.
- , , , , , , , , , , . 2004. Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 6: 229–240.
- , , . 2003. Basic helix-loop-helix factors in cortical development. Neuron 39: 13–25.
- . 1998. Combinatorial Gli gene function in floor plate and neuronal inductions by Sonic hedgehog. Development 125: 2203–2212.
- . 1999. Gli proteins encode context-dependent positive and negative functions: implications for development and disease. Development 126: 3205–3216.
- , , . 2002. Hedgehog-Gli signalling and the growth of the brain. Nat Rev Neurosci 3: 24–33.
- , , . 2003. The emergent design of the neural tube: prepattern, SHH morphogen and GLI code. Curr Opin Genet Dev 13: 513–521.
- , , . 2002. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer 2: 361–372.
- , , . 2004. Hedgehog-Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett 204: 145–157.
- , , . 1991. The zinc finger protein GLI transforms primary cells in cooperation with adenovirus E1A. Mol Cell Biol 11: 1724–1728.
- , , . 1991. In situ hybridization with single-stranded RNA probes to demonstrate infrequently elevated gli mRNA and no increased ras mRNA levels in meningiomas and astrocytomas. Cancer Lett 57: 243–253.
- , . 2005. In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mechanisms of Development 122: 223–230.
- , , , , , , , , , . 2004. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci U S A 101: 12561–12566.
- , , , , . 1999. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126: 3915–3924.
- , , , , . 1999. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc Natl Acad Sci U S A 96: 2880–2884.
- , , , , , , , , . 2004 Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer 3: 29.
- , , , , , , . 2003. Identification of a cancer stem cell in human brain tumors. Cancer Res 63: 5821–5828.
- , , , , , , , , . 2004. Identification of human brain tumour initiating cells. Nature 432: 396–401.
- , , , , , . 2001. Distinct sites of origin of oligodendrocytes and somatic motoneurons in the chick spinal cord: oligodendrocytes arise from Nkx2.2-expressing progenitors by a Shh-dependent mechanism. Development 128: 1369–1379.
- , , , , , , , , , , . 1999. Characterization of the human suppressor of fused,a negative regulator of the zinc-finger transcription factor Gli. J Cell Sci 112: 4437–4448.
- , . 1994. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 76: 89–102.
- , , , , , , , . 2000. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406: 1005–1009.
- , . 2004a. Rapid clearance of psoriatic skin lesions induced by topical cyclopamine. A preliminary proof of concept study. Dermatology 209: 126–131.
- , . 2004b. Induction of the differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur J Dermatol 14: 96–102.
- , , , , , , , , , , , , , , , , , , . 2002. Mutations in SUFU predispose to medulloblastoma. Nat Genet 31: 306–310.
- . 1999. CNS development: the obscure origins of adult stem cells. Curr Biol 9: R397–R399.
- . 2001. The development of neural stem cells. Nature 414: 112–117.
- , . 1999. Stem cells in the adult mammalian central nervous system. Curr Opin Neurobiol 9: 135–141.
- , , , , , , , , , , , , , . 2003. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425: 851–856.
- , , , . 1999. Gli3 is required for Emx gene expression during dorsal telencephalon development. Development 126: 3561–3571.
- , , , , , . 2003. Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog. Science 301: 843–846.
- , , . 2000. Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toes(J). Dev Biol 217: 254–265.
- , , , , , . 1999. Discrete localizations of hedgehog signalling components in the developing and adult rat nervous system. Eur J Neurosci 11: 3199–3214.
- , , , , , . 1999. Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon. Dev Biol 208: 166–188.
- , . 2002. Intrastriatal injection of sonic hedgehog reduces behavioral impairment in a rat model of Parkinson's disease. Exp Neurol 173: 95–104.
- , , , , , , . 2005. Zebrafish Gli3 functions as both an activator and a repressor in Hedgehog signaling. Dev Biol 277: 537–556.
- , , , , , , , , , . 1999. Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis. Nat Neurosci 2: 246–253.
- , , , , , , , , , . 1999. Deletion analysis of the adenomatous polyposis coli and PTCH gene loci in patients with sporadic and nevoid basal cell carcinoma syndrome-associated medulloblastoma. Cancer 85: 2662–2667.
- . 1999. Purkinje-cell-derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr Biol 9: 445–448.
- , , , , , , , . 1995. Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein. Nat Med 1: 1184–1188.
- , , . 2000. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100: 423–434.
- , . 2001. Genetic regulation of cerebellar development. Nat Rev Neurosci 2: 484–491.
- , , , , , . 2003. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422: 313–317.
- , . 1999. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22: 103–114.
- , , . 2001. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res 61: 513–516.
- . 2003. Sonic hedgehog in normal and neoplastic proliferation: insight gained from human tumors and animal models. Curr Opin Genet Dev 13: 34–42.
- , , , , , , , , , , . 2003. Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci U S A 100: 4616–4621.
- , , , , . 1997. 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 57: 2581–2585.
- , , . 1994. A search for gli expression in tumors of the central nervous system. Pediatr Neurosurg 20: 178–182.
- , , , , , , . 2001. A role of PDGFRalpha in basal cell carcinoma proliferation. Proc Natl Acad Sci U S A 98: 9255–9259.
- , , , , , , , , , , , , . 1998. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391: 90–92.
- , , , , . 1998. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93: 755–766.

1932-846X/asset/NEU_left.gif?v=1&s=fa3435fc99d6ef80f2fed53e67b3501cc978cb90)