Skip to main content
SpringerLink
Log in

Smoothened, Stem Cell Maintenance and Brain Diseases

  • Chapter
  • First Online:
The Smoothened Receptor in Cancer and Regenerative Medicine

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 16))

Abstract

The Smoothened (Smo) receptor is a key transducer of the Sonic Hedgehog (Shh) signaling pathway in the brain. Recent studies in rodents have highlighted its major role in the maintenance of neural stem and progenitor cells in the two main neurogenic niches of the adult brain: the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. Smo may also regulate brain responses to various injuries, and its modulation in the primary cilia of brain cells is essential for regulating Shh signals. Recent clinical trials have underlined the therapeutic value of some Smo antagonists for the treatment of Hedgehog-linked medulloblastomas. Here, we review recent findings on the roles of Smo in the adult brain, and unravel research on the clinical implications for the treatment of brain diseases, that are increasingly under investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

aNSC:

Activated neural stem cell

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

CNS:

Central nervous system

DG:

Dentate Gyrus

Dhh:

Desert Hedgehog

DS:

Down syndrome

EGFR:

Epidermal growth factor receptor

Gas1:

Growth arrest-specific 1 protein

GCL:

Granular cell layer

GCP:

Cerebellar granule cell precursor

GDNF:

Glial cell line-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

GLAST:

Astrocyte-specific glutamate transporter

GPCR:

G-protein-coupled receptor

Hh:

Hedgehog

HIP:

Hedgehog-interacting protein

Ihh:

Indian Hedgehog

JS:

Joubert syndrome

LPC:

Lysophosphatidyl choline

LV:

Lateral ventricle

MKS:

Meckel syndrome

NG2:

Neuron-glial antigen 2

NMDA:

N-methyl-d-aspartate

NSC:

Neural stem cell

OB:

Olfactory bulb

OL:

Oligodendrocyte

OPC:

Oligodendrocyte precursor cell

PlGF:

Placental growth factor

Ptc:

Patched

qNSC:

Quiescent neural stem cell

RMS:

Rostral migratory stream

SGZ:

Subgranular zone

Shh:

Sonic Hedgehog

ShhN:

Aminoterminal fragment of Shh

Smo:

Smoothened

Sufu:

Suppressor of fused

SVZ:

Subventricular zone

TAC:

Transit-amplifying cell

References

  1. Dessaud E, McMahon AP, Briscoe J (2008) Pattern formation in the vertebrate neural tube: a Sonic Hedgehog morphogen-regulated transcriptional network. Development 135:2489–2503

    CAS  Google Scholar 

  2. Varjosalo M, Taipale J (2008) Hedgehog: functions and mechanisms. Genes Dev 22:2454–2472

    CAS  Google Scholar 

  3. Briscoe J, Therond PP (2013) The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev 14:416–429

    Google Scholar 

  4. Coni S, Infante P, Gulino A (2013) Control of stem cells and cancer stem cells by Hedgehog signaling: pharmacologic clues from pathway dissection. Biochem Pharmacol 85:623–628

    CAS  Google Scholar 

  5. Ruat M, Roudaut H, Ferent J, Traiffort E (2012) Hedgehog trafficking, cilia and brain functions. Differentiation 83:S97–S104

    CAS  Google Scholar 

  6. Charytoniuk D, Porcel B, Rodriguez Gomez J, Faure H, Ruat M, Traiffort E (2002) Sonic Hedgehog signalling in the developing and adult brain. J Physiol Paris 96:9–16

    CAS  Google Scholar 

  7. Borzillo GV, Lippa B (2005) The Hedgehog signaling pathway as a target for anticancer drug discovery. Curr Top Med Chem 5:147–157

    CAS  Google Scholar 

  8. Traiffort E, Angot E, Ruat M (2010) Sonic Hedgehog signaling in the mammalian brain. J Neurochem 113:576–590

    CAS  Google Scholar 

  9. Alvarez-Buylla A, Ihrie RA (2014) Sonic Hedgehog signaling in the postnatal brain. Semin Cell Dev Biol 33:105–111

    CAS  Google Scholar 

  10. Han YG, Alvarez-Buylla A (2010) Role of primary cilia in brain development and cancer. Curr Opin Neurobiol 20:58–67

    CAS  Google Scholar 

  11. Suh H, Deng W, Gage FH (2009) Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 25:253–275

    CAS  Google Scholar 

  12. Ng JM, Curran T (2011) The Hedgehog’s tale: developing strategies for targeting cancer. Nat Rev Cancer 11:493–501

    CAS  Google Scholar 

  13. Low JA, de Sauvage FJ (2010) Clinical experience with Hedgehog pathway inhibitors. J Clin Oncol 28:5321–5326

    CAS  Google Scholar 

  14. Heretsch P, Tzagkaroulaki L, Giannis A (2010) Modulators of the Hedgehog signaling pathway. Bioorg Med Chem 18:6613–6624

    CAS  Google Scholar 

  15. Mas C, Ruiz i Altaba A (2010) Small molecule modulation of HH-GLI signaling: current leads, trials and tribulations. Biochem Pharmacol 80:712–723

    CAS  Google Scholar 

  16. Hadden MK (2013) Hedgehog pathway inhibitors: a patent review (2009–present). Expert Opin Ther Pat 23:345–361

    CAS  Google Scholar 

  17. Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426:83–87

    CAS  Google Scholar 

  18. Goetz SC, Anderson KV (2010) The primary cilium: a signalling centre during vertebrate development. Nat Rev Genet 11:331–344

    CAS  Google Scholar 

  19. Louvi A, Grove EA (2011) Cilia in the CNS: the quiet organelle claims center stage. Neuron 69:1046–1060

    CAS  Google Scholar 

  20. Simpson F, Kerr MC, Wicking C (2009) Trafficking, development and Hedgehog. Mech Dev 126:279–288

    CAS  Google Scholar 

  21. Pepinsky RB, Zeng C, Wen D, Rayhorn P, Baker DP, Williams KP, Bixler SA, Ambrose CM, Garber EA, Miatkowski K, Taylor FR, Wang EA, Galdes A (1998) Identification of a palmitic acid-modified form of human Sonic Hedgehog. J Biol Chem 273:14037–14045

    CAS  Google Scholar 

  22. Traiffort E, Moya KL, Faure H, Hassig R, Ruat M (2001) High expression and anterograde axonal transport of aminoterminal Sonic Hedgehog in the adult hamster brain. Eur J Neurosci 14:839–850

    CAS  Google Scholar 

  23. Coulombe J, Traiffort E, Loulier K, Faure H, Ruat M (2004) Hedgehog interacting protein in the mature brain: membrane-associated and soluble forms. Mol Cell Neurosci 25:323–333

    CAS  Google Scholar 

  24. Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ, Jackson PK (2013) The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic Hedgehog pathway via cAMP signaling. Cell 152:210–223

    CAS  Google Scholar 

  25. Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M, Wang J, Chen W, Lefkowitz RJ (2008) Beta-arrestin-mediated localization of smoothened to the primary cilium. Science 320:1777–1781

    CAS  Google Scholar 

  26. Dorn KV, Hughes CE, Rohatgi R (2012) A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev Cell 23:823–835

    CAS  Google Scholar 

  27. Milenkovic L, Scott MP, Rohatgi R (2009) Lateral transport of Smoothened from the plasma membrane to the membrane of the cilium. J Cell Biol 187:365–374

    CAS  Google Scholar 

  28. Ruiz i Altaba A, Mas C, Stecca B (2007) The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol 17:438–447

    CAS  Google Scholar 

  29. Riobo NA, Manning DR (2007) Pathways of signal transduction employed by vertebrate Hedgehogs. Biochem J 403:369–379

    CAS  Google Scholar 

  30. Allen BL, Song JY, Izzi L, Althaus IW, Kang JS, Charron F, Krauss RS, McMahon AP (2011) Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell 20:775–787

    CAS  Google Scholar 

  31. Izzi L, Levesque M, Morin S, Laniel D, Wilkes BC, Mille F, Krauss RS, McMahon AP, Allen BL, Charron F (2011) Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation. Dev Cell 20:788–801

    CAS  Google Scholar 

  32. Yam PT, Langlois SD, Morin S, Charron F (2009) Sonic Hedgehog guides axons through a noncanonical, Src-family-kinase-dependent signaling pathway. Neuron 62:349–362

    CAS  Google Scholar 

  33. Belgacem YH, Borodinsky LN (2011) Sonic Hedgehog signaling is decoded by calcium spike activity in the developing spinal cord. Proc Natl Acad Sci U S A 108:4482–4487

    CAS  Google Scholar 

  34. Teperino R, Amann S, Bayer M, McGee SL, Loipetzberger A, Connor T, Jaeger C, Kammerer B, Winter L, Wiche G, Dalgaard K, Selvaraj M, Gaster M, Lee-Young RS, Febbraio MA, Knauf C, Cani PD, Aberger F, Penninger JM, Pospisilik JA, Esterbauer H (2012) Hedgehog partial agonism drives Warburg-like metabolism in muscle and brown fat. Cell 151:414–426

    CAS  Google Scholar 

  35. Polizio AH, Chinchilla P, Chen X, Kim S, Manning DR, Riobo NA (2011) Heterotrimeric Gi proteins link Hedgehog signaling to activation of Rho small GTPases to promote fibroblast migration. J Biol Chem 286:19589–19596

    CAS  Google Scholar 

  36. Jenkins D (2009) Hedgehog signalling: emerging evidence for non-canonical pathways. Cell Signal 21:1023–1034

    CAS  Google Scholar 

  37. Javelaud D, Pierrat MJ, Mauviel A (2012) Crosstalk between TGF-beta and Hedgehog signaling in cancer. FEBS Lett 586:2016–2025

    CAS  Google Scholar 

  38. Yam PT, Charron F (2013) Signaling mechanisms of non-conventional axon guidance cues: the Shh, BMP and Wnt morphogens. Curr Opin Neurobiol 23:965–973

    CAS  Google Scholar 

  39. Brennan D, Chen X, Cheng L, Mahoney M, Riobo NA (2012) Noncanonical Hedgehog signaling. Vitam Horm 88:55–72

    CAS  Google Scholar 

  40. Bettencourt-Dias M, Hildebrandt F, Pellman D, Woods G, Godinho SA (2011) Centrosomes and cilia in human disease. Trends Genet 27:307–315

    CAS  Google Scholar 

  41. Rosenbaum JL, Witman GB (2002) Intraflagellar transport. Nat Rev 3:813–825

    CAS  Google Scholar 

  42. Taschner M, Bhogaraju S, Lorentzen E (2011) Architecture and function of IFT complex proteins in ciliogenesis. Differentiation 83:S12–S22

    Google Scholar 

  43. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF (2005) Vertebrate smoothened functions at the primary cilium. Nature 437:1018–1021

    CAS  Google Scholar 

  44. Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1:e53

    Google Scholar 

  45. Huangfu D, Anderson KV (2006) Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 13(3):3–14

    Google Scholar 

  46. Rohatgi R, Milenkovic L, Scott MP (2007) Patched1 regulates Hedgehog signaling at the primary cilium. Science 317:372–376

    CAS  Google Scholar 

  47. Chamberlain CE, Jeong J, Guo C, Allen BL, McMahon AP (2008) Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning. Development 135:1097–1106

    CAS  Google Scholar 

  48. Friedland-Little JM, Hoffmann AD, Ocbina PJ, Peterson MA, Bosman JD, Chen Y, Cheng SY, Anderson KV, Moskowitz IP (2011) A novel murine allele of intraflagellar transport protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum Mol Genet 20:3725–3737

    CAS  Google Scholar 

  49. Ayers KL, Therond PP (2010) Evaluating smoothened as a G-protein-coupled receptor for Hedgehog signalling. Trends Cell Biol 20:287–298

    CAS  Google Scholar 

  50. Ingham PW, Nakano Y, Seger C (2011) Mechanisms and functions of Hedgehog signalling across the metazoa. Nat Rev Genet 12:393–406

    CAS  Google Scholar 

  51. Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K, Davis M, Scales SJ, Solloway MJ, de Sauvage FJ, Peterson AS (2009) The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol 19:1320–1326

    CAS  Google Scholar 

  52. Liem KF Jr, He M, Ocbina PJ, Anderson KV (2009) Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic Hedgehog signaling. Proc Natl Acad Sci U S A 106:13377–13382

    CAS  Google Scholar 

  53. Kim J, Kato M, Beachy PA (2009) Gli2 trafficking links Hedgehog-dependent activation of smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci U S A 106(51):21666–21671

    CAS  Google Scholar 

  54. Doetsch F, Caille I, Lim DA, Garcia-Verdugo JM, Alvarez-Buylla A (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97:703–716

    CAS  Google Scholar 

  55. El Waly B, Macchi M, Cayre M, Durbec P (2014) Oligodendrogenesis in the normal and pathological central nervous system. Front Neurosci 8:145

    Google Scholar 

  56. Ferent J, Zimmer C, Durbec P, Ruat M, Traiffort E (2013) Sonic Hedgehog signaling is a positive oligodendrocyte regulator during demyelination. J Neurosci 33:1759–1772

    CAS  Google Scholar 

  57. Charytoniuk D, Traiffort E, Hantraye P, Hermel JM, Galdes A, Ruat M (2002) Intrastriatal Sonic Hedgehog injection increases patched transcript levels in the adult rat subventricular zone. Eur J Neurosci 16:2351–2357

    CAS  Google Scholar 

  58. Ahn S, Joyner AL (2005) In vivo analysis of quiescent adult neural stem cells responding to Sonic Hedgehog. Nature 437:894–897

    CAS  Google Scholar 

  59. Ferent J, Cochard L, Faure H, Taddei M, Hahn H, Ruat M, Traiffort E (2014) Genetic activation of Hedgehog signaling unbalances the rate of neural stem cell renewal by increasing symmetric divisions. Stem Cell Rep 3:312–323

    CAS  Google Scholar 

  60. Angot E, Loulier K, Nguyen-Ba-Charvet KT, Gadeau AP, Ruat M, Traiffort E (2008) Chemoattractive activity of Sonic Hedgehog in the adult subventricular zone modulates the number of neural precursors reaching the olfactory bulb. Stem Cells 26:2311–2320

    CAS  Google Scholar 

  61. Aimone JB, Li Y, Lee SW, Clemenson GD, Deng W, Gage FH (2014) Regulation and function of adult neurogenesis: from genes to cognition. Physiol Rev 94:991–1026

    CAS  Google Scholar 

  62. Christian KM, Song H, Ming GL (2014) Functions and dysfunctions of adult hippocampal neurogenesis. Annu Rev Neurosci 37:243–262

    CAS  Google Scholar 

  63. Han YG, Spassky N, Romaguera-Ros M, Garcia-Verdugo JM, Aguilar A, Schneider-Maunoury S, Alvarez-Buylla A (2008) Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11:277–284

    CAS  Google Scholar 

  64. Breunig JJ, Sarkisian MR, Arellano JI, Morozov YM, Ayoub AE, Sojitra S, Wang B, Flavell RA, Rakic P, Town T (2008) Primary cilia regulate hippocampal neurogenesis by mediating Sonic Hedgehog signaling. Proc Natl Acad Sci U S A 105:13127–13132

    CAS  Google Scholar 

  65. Lai K, Kaspar BK, Gage FH, Schaffer DV (2003) Sonic Hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6:21–27

    CAS  Google Scholar 

  66. Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184

    CAS  Google Scholar 

  67. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660

    CAS  Google Scholar 

  68. Silva-Vargas V, Crouch EE, Doetsch F (2013) Adult neural stem cells and their niche: a dynamic duo during homeostasis, regeneration, and aging. Curr Opin Neurobiol 23:935–942

    CAS  Google Scholar 

  69. Pereira Dias G, Hollywood R, Bevilaqua MC, da Luz AC, Hindges R, Nardi AE, Thuret S (2014) Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms. Neuro Oncol 16:476–492

    Google Scholar 

  70. Traiffort E, Charytoniuk D, Watroba L, Faure H, Sales N, Ruat M (1999) Discrete localizations of Hedgehog signalling components in the developing and adult rat nervous system. Eur J Neurosci 11:3199–3214

    CAS  Google Scholar 

  71. Traiffort E, Charytoniuk DA, Faure H, Ruat M (1998) Regional distribution of Sonic Hedgehog, patched, and smoothened mRNA in the adult rat brain. J Neurochem 70:1327–1330

    CAS  Google Scholar 

  72. Charytoniuk DA, Traiffort E, Faure H, Salès N, Ruat M (1998) Localisation of cells expressing patched and smoothened mRNA in adult mouse and rat brain. Eur J Neurosci 10:16738

    Google Scholar 

  73. Ihrie RA, Shah JK, Harwell CC, Levine JH, Guinto CD, Lezameta M, Kriegstein AR, Alvarez-Buylla A (2011) Persistent Sonic Hedgehog signaling in adult brain determines neural stem cell positional identity. Neuron 71:250–262

    CAS  Google Scholar 

  74. Petrova R, Garcia AD, Joyner AL (2013) Titration of GLI3 repressor activity by Sonic Hedgehog signaling is critical for maintaining multiple adult neural stem cell and astrocyte functions. J Neurosci 33:17490–17505

    CAS  Google Scholar 

  75. Roudaut H, Traiffort E, Gorojankina T, Vincent L, Faure H, Schoenfelder A, Mann A, Manetti F, Solinas A, Taddei M, Ruat M (2011) Identification and mechanism of action of the acylguanidine MRT-83, a novel potent Smoothened antagonist. Mol Pharmacol 79:453–460

    CAS  Google Scholar 

  76. Machold R, Hayashi S, Rutlin M, Muzumdar MD, Nery S, Corbin JG, Gritli-Linde A, Dellovade T, Porter JA, Rubin LL, Dudek H, McMahon AP, Fishell G (2003) Sonic Hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39:937–950

    CAS  Google Scholar 

  77. Palma V, Lim DA, Dahmane N, Sanchez P, Brionne TC, Herzberg CD, Gitton Y, Carleton A, Alvarez-Buylla A, Ruiz i Altaba A (2005) Sonic Hedgehog controls stem cell behavior in the postnatal and adult brain. Development 132:335–344

    CAS  Google Scholar 

  78. Banerjee SB, Rajendran R, Dias BG, Ladiwala U, Tole S, Vaidya VA (2005) Recruitment of the Sonic Hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis. Eur J Neurosci 22:1570–1580

    Google Scholar 

  79. Balordi F, Fishell G (2007) Hedgehog signaling in the subventricular zone is required for both the maintenance of stem cells and the migration of newborn neurons. J Neurosci 27:5936–5947

    CAS  Google Scholar 

  80. Balordi F, Fishell G (2007) Mosaic removal of Hedgehog signaling in the adult SVZ reveals that the residual wild-type stem cells have a limited capacity for self-renewal. J Neurosci 27:14248–14259

    CAS  Google Scholar 

  81. Merkle FT, Fuentealba LC, Sanders TA, Magno L, Kessaris N, Alvarez-Buylla A (2014) Adult neural stem cells in distinct microdomains generate previously unknown interneuron types. Nat Neurosci 17:207–214

    CAS  Google Scholar 

  82. Brill MS, Ninkovic J, Winpenny E, Hodge RD, Ozen I, Yang R, Lepier A, Gascon S, Erdelyi F, Szabo G, Parras C, Guillemot F, Frotscher M, Berninger B, Hevner RF, Raineteau O, Gotz M (2009) Adult generation of glutamatergic olfactory bulb interneurons. Nat Neurosci 12:1524–1533

    CAS  Google Scholar 

  83. Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193

    CAS  Google Scholar 

  84. Myers BR, Sever N, Chong YC, Kim J, Belani JD, Rychnovsky S, Bazan JF, Beachy PA (2013) Hedgehog pathway modulation by multiple lipid binding sites on the smoothened effector of signal response. Dev Cell 26:346–357

    CAS  Google Scholar 

  85. Nachtergaele S, Mydock LK, Krishnan K, Rammohan J, Schlesinger PH, Covey DF, Rohatgi R (2012) Oxysterols are allosteric activators of the oncoprotein Smoothened. Nat Chem Biol 8:211–220

    CAS  Google Scholar 

  86. Nachtergaele S, Whalen DM, Mydock LK, Zhao Z, Malinauskas T, Krishnan K, Ingham PW, Covey DF, Siebold C, Rohatgi R (2013) Structure and function of the smoothened extracellular domain in vertebrate Hedgehog signaling. Elife 2:e01340

    Google Scholar 

  87. Nedelcu D, Liu J, Xu Y, Jao C, Salic A (2013) Oxysterol binding to the extracellular domain of smoothened in Hedgehog signaling. Nat Chem Biol 9:557–564

    CAS  Google Scholar 

  88. Wang J, Lu J, Bond MC, Chen M, Ren XR, Lyerly HK, Barak LS, Chen W (2010) Identification of select glucocorticoids as smoothened agonists: potential utility for regenerative medicine. Proc Natl Acad Sci U S A 107:9323–9328

    CAS  Google Scholar 

  89. Favaro R, Valotta M, Ferri AL, Latorre E, Mariani J, Giachino C, Lancini C, Tosetti V, Ottolenghi S, Taylor V, Nicolis SK (2009) Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci 12:1248–1256

    CAS  Google Scholar 

  90. Li G, Fang L, Fernandez G, Pleasure SJ (2013) The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus. Neuron 78:658–672

    CAS  Google Scholar 

  91. Takeda S, Yonekawa Y, Tanaka Y, Okada Y, Nonaka S, Hirokawa N (1999) Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis. J Cell Biol 145:825–836

    CAS  Google Scholar 

  92. Rohatgi R, Milenkovic L, Corcoran RB, Scott MP (2009) Hedgehog signal transduction by smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci U S A 106:3196–3201

    CAS  Google Scholar 

  93. Amador-Arjona A, Elliott J, Miller A, Ginbey A, Pazour GJ, Enikolopov G, Roberts AJ, Terskikh AV (2011) Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory. J Neurosci 31:9933–9944

    CAS  Google Scholar 

  94. Town T, Breunig JJ, Sarkisian MR, Spilianakis C, Ayoub AE, Liu X, Ferrandino AF, Gallagher AR, Li MO, Rakic P, Flavell RA (2008) The stumpy gene is required for mammalian ciliogenesis. Proc Natl Acad Sci U S A 105:2853–2858

    CAS  Google Scholar 

  95. Galvin KE, Ye H, Erstad DJ, Feddersen R, Wetmore C (2008) Gli1 induces G2/M arrest and apoptosis in hippocampal but not tumor-derived neural stem cells. Stem Cells 26:1027–1036

    CAS  Google Scholar 

  96. Bilkei-Gorzo A (2014) Genetic mouse models of brain ageing and Alzheimer’s disease. Pharmacol Ther 142:244–257

    CAS  Google Scholar 

  97. He P, Staufenbiel M, Li R, Shen Y (2014) Deficiency of Patched 1-induced Gli1 signal transduction results in astrogenesis in Swedish mutated APP transgenic mice. Hum Mol Genet 23(24):6512–6527

    CAS  Google Scholar 

  98. Masdeu C, Bernard V, Faure H, Traiffort E, Ruat M (2007) Distribution of Smoothened at hippocampal mossy fiber synapses. Neuroreport 18:395–399

    Google Scholar 

  99. Petralia RS, Schwartz CM, Wang YX, Mattson MP, Yao PJ (2011) Subcellular localization of patched and smoothened, the receptors for Sonic Hedgehog signaling, in the hippocampal neuron. J Comp Neurol 519:3684–3699

    CAS  Google Scholar 

  100. Jones DT, Jager N, Kool M, Zichner T, Hutter B et al (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488:100–105

    CAS  Google Scholar 

  101. Scales SJ, de Sauvage FJ (2009) Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30:303–312

    CAS  Google Scholar 

  102. Pritchard JI, Olson JM (2008) Methylation of PTCH1, the Patched-1 gene, in a panel of primary medulloblastomas. Cancer Genet Cytogenet 180:47–50

    CAS  Google Scholar 

  103. Corcoran RB, Bachar Raveh T, Barakat MT, Lee EY, Scott MP (2008) Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice. Cancer Res 68:8788–8795

    CAS  Google Scholar 

  104. Parathath SR, Mainwaring LA, Fernandez LA, Campbell DO, Kenney AM (2008) Insulin receptor substrate 1 is an effector of Sonic Hedgehog mitogenic signaling in cerebellar neural precursors. Development 135:3291–3300

    CAS  Google Scholar 

  105. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, Schuller U, Machold R, Fishell G, Rowitch DH, Wainwright BJ, Wechsler-Reya RJ (2008) Medulloblastoma can be initiated by deletion of patched in lineage-restricted progenitors or stem cells. Cancer Cell 14:135–145

    CAS  Google Scholar 

  106. Li P, Du F, Yuelling LW, Lin T, Muradimova RE, Tricarico R, Wang J, Enikolopov G, Bellacosa A, Wechsler-Reya RJ, Yang ZJ (2013) A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity. Nat Neurosci 16:1737–1744

    CAS  Google Scholar 

  107. Amakye D, Jagani Z, Dorsch M (2013) Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat Med 19:1410–1422

    CAS  Google Scholar 

  108. Dahmane N, Ruiz-i-Altaba A (1999) Sonic Hedgehog regulates the growth and patterning of the cerebellum. Development 126:3089–3100

    Google Scholar 

  109. Rowitch DH, S-J B, Lee SM, Flax JD, Snyder EY, McMahon AP (1999) Sonic Hedgehog regulates proliferation and inhibits differentiation of CNS precursor cells. J Neurosci 19:8954–8965

    CAS  Google Scholar 

  110. Petralia RS, Wang YX, Mattson MP, Yao PJ (2012) Subcellular distribution of patched and smoothened in the cerebellar neurons. Cerebellum 11:972–981

    Google Scholar 

  111. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C et al (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065–1076

    CAS  Google Scholar 

  112. Han YG, Kim HJ, Dlugosz AA, Ellison DW, Gilbertson RJ, Alvarez-Buylla A (2009) Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 15:1062–1065

    CAS  Google Scholar 

  113. Wong SY, Seol AD, So PL, Ermilov AN, Bichakjian CK, Epstein EH Jr, Dlugosz AA, Reiter JF (2009) Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat Med 15:1055–1061

    CAS  Google Scholar 

  114. Aguilar A, Meunier A, Strehl L, Martinovic J, Bonniere M, Attie-Bitach T, Encha-Razavi F, Spassky N (2012) Analysis of human samples reveals impaired SHH-dependent cerebellar development in Joubert syndrome/Meckel syndrome. Proc Natl Acad Sci U S A 109:16951–16956

    CAS  Google Scholar 

  115. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, Holcomb T, Stinson J, Gould SE, Coleman B, LoRusso PM, Von Hoff DD, de Sauvage FJ, Low JA (2009) Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449. N Engl J Med 361:1173–1178

    CAS  Google Scholar 

  116. Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ (2009) Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326:572–574

    CAS  Google Scholar 

  117. Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, Hsiao K, Yuan J, Green J, Ospina B, Yu Q, Ostrom L, Fordjour P, Anderson DL, Monahan JE, Kelleher JF, Peukert S, Pan S, Wu X, Maira SM, Garcia-Echeverria C, Briggs KJ, Watkins DN, Yao YM, Lengauer C, Warmuth M, Sellers WR, Dorsch M (2010) Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med 2:51–70

    Google Scholar 

  118. Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of Hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev 16:2743–2748

    CAS  Google Scholar 

  119. Costa AC, Scott-McKean JJ (2013) Prospects for improving brain function in individuals with down syndrome. CNS Drugs 27:679–702

    CAS  Google Scholar 

  120. Das I, Park JM, Shin JH, Jeon SK, Lorenzi H, Linden DJ, Worley PF, Reeves RH (2013) Hedgehog agonist therapy corrects structural and cognitive deficits in a down syndrome mouse model. Sci Transl Med 5:201ra120

    Google Scholar 

  121. Trazzi S, Fuchs C, Valli E, Perini G, Bartesaghi R, Ciani E (2013) The amyloid precursor protein (APP) triplicated gene impairs neuronal precursor differentiation and neurite development through two different domains in the Ts65Dn mouse model for Down syndrome. J Biol Chem 288:20817–20829

    CAS  Google Scholar 

  122. Trazzi S, Mitrugno VM, Valli E, Fuchs C, Rizzi S, Guidi S, Perini G, Bartesaghi R, Ciani E (2011) APP-dependent up-regulation of Ptch1 underlies proliferation impairment of neural precursors in Down syndrome. Hum Mol Genet 20:1560–1573

    CAS  Google Scholar 

  123. Tsuboi K, Shults CW (2002) Intrastriatal injection of Sonic Hedgehog reduces behavioral impairment in a rat model of Parkinson’s disease. Exp Neurol 173:95–104

    CAS  Google Scholar 

  124. Dass B, Iravani MM, Jackson MJ, Engber TM, Galdes A, Jenner P (2002) Behavioural and immunohistochemical changes following supranigral administration of Sonic Hedgehog in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. Neuroscience 114:99–109

    CAS  Google Scholar 

  125. Gonzalez-Reyes LE, Verbitsky M, Blesa J, Jackson-Lewis V, Paredes D, Tillack K, Phani S, Kramer ER, Przedborski S, Kottmann AH (2012) Sonic Hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit. Neuron 75:306–319

    CAS  Google Scholar 

  126. Dimou L, Gotz M (2014) Glial cells as progenitors and stem cells: new roles in the healthy and diseased brain. Physiol Rev 94:709–737

    CAS  Google Scholar 

  127. Garcia AD, Petrova R, Eng L, Joyner AL (2010) Sonic Hedgehog regulates discrete populations of astrocytes in the adult mouse forebrain. J Neurosci 30:13597–13608

    CAS  Google Scholar 

  128. Sirko S, Behrendt G, Johansson PA, Tripathi P, Costa M, Bek S, Heinrich C, Tiedt S, Colak D, Dichgans M, Fischer IR, Plesnila N, Staufenbiel M, Haass C, Snapyan M, Saghatelyan A, Tsai LH, Fischer A, Grobe K, Dimou L, Gotz M (2013) Reactive glia in the injured brain acquire stem cell properties in response to Sonic Hedgehog [corrected]. Cell Stem Cell 12:426–439

    CAS  Google Scholar 

  129. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G (2013) In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell 14:188–202

    Google Scholar 

  130. Edgar N, Sibille E (2012) A putative functional role for oligodendrocytes in mood regulation. Transl Psychiatry 2:e109

    CAS  Google Scholar 

  131. Dawson MR, Polito A, Levine JM, Reynolds R (2003) NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol Cell Neurosci 24:476–488

    CAS  Google Scholar 

  132. Menn B, Garcia-Verdugo JM, Yaschine C, Gonzalez-Perez O, Rowitch D, Alvarez-Buylla A (2006) Origin of oligodendrocytes in the subventricular zone of the adult brain. J Neurosci 26:7907–7918

    CAS  Google Scholar 

  133. Loulier K, Ruat M, Traiffort E (2006) Increase of proliferating oligodendroglial progenitors in the adult mouse brain upon Sonic Hedgehog delivery in the lateral ventricle. J Neurochem 98:530–542

    CAS  Google Scholar 

  134. Mierzwa AJ, Sullivan GM, Beer LA, Ahn S, Armstrong RC (2014) Comparison of cortical and white matter traumatic brain injury models reveals differential effects in the subventricular zone and divergent Sonic Hedgehog signaling pathways in neuroblasts and oligodendrocyte progenitors. ASN Neuro. doi:10.1177/1759091414551782

    Google Scholar 

  135. Akazawa C, Tsuzuki H, Nakamura Y, Sasaki Y, Ohsaki K, Nakamura S, Arakawa Y, Kohsaka S (2004) The upregulated expression of Sonic Hedgehog in motor neurons after rat facial nerve axotomy. J Neurosci 24:7923–7930

    CAS  Google Scholar 

  136. Heine VM, Rowitch DH (2009) Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11betaHSD2-dependent mechanism. J Clin Invest 119:267–277

    CAS  Google Scholar 

  137. Bezard E, Baufreton J, Owens G, Crossman AR, Dudek H, Taupignon A, Brotchie JM (2003) Sonic Hedgehog is a neuromodulator in the adult subthalamic nucleus. FASEB J 17:2337–2338

    CAS  Google Scholar 

  138. Pascual O, Traiffort E, Baker DP, Galdes A, Ruat M, Champagnat J (2005) Sonic Hedgehog signalling in neurons of adult ventrolateral nucleus tractus solitarius. Eur J Neurosci 22:389–396

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecules and Circuits Department, Signal Transduction and Developmental Neuropharmacology Team, NeuroPSI Institute, CNRS, UMR 9197, 1 Avenue de la Terrasse, 91198, Gif-sur-Yvette, France

    Martial Ruat, Hélène Faure & Mathieu Daynac

Authors
  1. Martial Ruat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hélène Faure
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mathieu Daynac
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martial Ruat .

Editor information

Editors and Affiliations

  1. Institute of Neurosciences Paris-Saclay (Neuro-PSI), National Centre for Scientific Research, Gif-Yvette, France

    Martial Ruat

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Ruat, M., Faure, H., Daynac, M. (2014). Smoothened, Stem Cell Maintenance and Brain Diseases. In: Ruat, M. (eds) The Smoothened Receptor in Cancer and Regenerative Medicine. Topics in Medicinal Chemistry, vol 16. Springer, Cham. https://doi.org/10.1007/7355_2014_83

Download citation

Publish with us

Policies and ethics

Search

Navigation