Acta Neuropathologica

, Volume 123, Issue 5, pp 695–709 | Cite as

Joubert syndrome: brain and spinal cord malformations in genotyped cases and implications for neurodevelopmental functions of primary cilia

  • Gordana Juric-Sekhar
  • Jonathan Adkins
  • Dan DohertyEmail author
  • Robert F. HevnerEmail author
Original Paper


Joubert syndrome (JS) is an autosomal recessive ciliopathy characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability. The brain is malformed, with severe vermian hypoplasia, fourth ventriculomegaly, and “molar tooth” appearance of the cerebral and superior cerebellar peduncles visible as consistent features on neuroimaging. Neuropathological studies, though few, suggest that several other brain and spinal cord structures, such as the dorsal cervicomedullary junction, may also be affected in at least some patients. Genetically, JS is heterogeneous, with mutations in 13 genes accounting for approximately 50% of patients. Here, we compare neuropathologic findings in five subjects with JS, including four with defined mutations in OFD1 (2 siblings), RPGRIP1L, or TCTN2. Characteristic findings in all JS genotypes included vermian hypoplasia, fragmented dentate and spinal trigeminal nuclei, hypoplastic pontine and inferior olivary nuclei, and nondecussation of corticospinal tracts. Other common findings, seen in multiple genotypes but not all subjects, were dorsal cervicomedullary heterotopia, nondecussation of superior cerebellar peduncles, enlarged arcuate nuclei, hypoplastic reticular formation, hypoplastic medial lemnisci, and dorsal spinal cord disorganization. Thus, while JS exhibits significant neuropathologic as well as genetic heterogeneity, no genotype–phenotype correlations are apparent as yet. Our findings suggest that primary cilia are important for neural patterning, progenitor proliferation, cell migration, and axon guidance in the developing human brain and spinal cord.


Joubert syndrome Ciliopathy Cerebellar malformation Vermis aplasia Brainstem malformation Spinal cord malformation 



We thank the families of described subjects for giving us permission to study their children. We also thank Drs. Joseph R. Siebert, Raj P. Kapur (Seattle Children’s Hospital and University of Washington, Seattle, WA), Robert E. Ruiz (The University of Michigan Hospitals, Ann Arbor, MI), Carol Petito (University of Miami, Miami, Fl), Mason Barr (University of Michigan) and colleagues from the Wayne County Medical Examiner’s Office (Romulus, MI) for important assistance to our research. Human tissue was obtained from the NICHD Brain and Tissue bank for Developmental Disorders at the University of Maryland, Baltimore, MD. D.D. was supported by KL2RR025015.


  1. 1.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249PubMedCrossRefGoogle Scholar
  2. 2.
    Altman NR, Naidich TP, Braffman BH (1992) Posterior fossa malformations. AJNR Am J Neuroradiol 13:691–724PubMedGoogle Scholar
  3. 3.
    Baala L, Romano S, Khaddour R, Saunier S, Smith UM, Audollent S, Ozilou C, Faivre L, Laurent N, Foliguet B, Munnich A, Lyonnet S, Salomon R, Encha-Razavi F, Gubler MC, Boddaert N, de Lonlay P, Johnson CA, Vekemans M, Antignac C, Attie-Bitach T (2007) The Meckel–Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am J Hum Genet 80:186–194PubMedCrossRefGoogle Scholar
  4. 4.
    Boltshauser E, Isler W (1977) Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. Neuropadiatrie 8:57–66PubMedCrossRefGoogle Scholar
  5. 5.
    Brancati F, Dallapiccola B, Valente EM (2010) Joubert syndrome and related disorders. Orphanet J Rare Dis 5:20PubMedCrossRefGoogle Scholar
  6. 6.
    Budny B, Chen W, Omran H et al (2006) A novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral-facial-digital type I syndrome. Hum Genet 120:171–178PubMedCrossRefGoogle Scholar
  7. 7.
    Calogero JA (1977) Vermian agenesis and unsegmented midbrain tectum. Case report. J Neurosurg 47:605–608PubMedCrossRefGoogle Scholar
  8. 8.
    Campbell S, Tsannatos C, Pearce JM (1984) The prenatal diagnosis of Joubert’s syndrome of familial agenesis of the cerebellar vermis. Prenat Diagn 4:391–395PubMedCrossRefGoogle Scholar
  9. 9.
    Caspary T, Larkins CE, Anderson KV (2007) The graded response to sonic hedgehog depends on cilia architecture. Develop Cell 12:767–778CrossRefGoogle Scholar
  10. 10.
    Chizhikov VV, Davenport J, Zhang Q et al (2007) Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J Neurosci 27:9780–9789PubMedCrossRefGoogle Scholar
  11. 11.
    Coene KL, Roepman R, Doherty D, Afroze B, Kroes HY, Letteboer SJ, Ngu LH, Budny B, van Wijk E, Gorden NT, Azhimi M, Thauvin-Robinet C, Veltman JA, Boink M, Kleefstra T, Cremers FP, van Bokhoven H, de Brouwer AP (2009) OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am J Hum Genet 85:465–481PubMedCrossRefGoogle Scholar
  12. 12.
    Dafinger C, Liebau MC, Elsayed SM, Hellenbroich Y, Boltshauser E, Korenke GC, Fabretti F, Janecke AR, Ebermann I, Nürnberg G, Nürnberg P, Zentgraf H, Koerber F, Addicks K, Elsobky E, Benzing T, Schermer B, Bolz HJ (2011) Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics. J Clin Invest 121:2662–2667PubMedCrossRefGoogle Scholar
  13. 13.
    Dahmane N, Sanchez P, Gitton Y, Palma V, Sun T, Beyna M, Weiner H, Ruiz i Altaba A (2001) The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis. Development 128:5201–5212PubMedGoogle Scholar
  14. 14.
    Delous M, Baala L, Salomon R, Laclef C, Vierkotten J, Tory K, Golzio C, Lacoste T, Besse L, Ozilou C, Moutkine I, Hellman NE, Anselme I, Silbermann F, Vesque C, Gerhardt C, Rattenberry E, Wolf MT, Gubler MC, Martinovic J, Encha-Razavi F, Boddaert N, Gonzales M, Macher MA, Nivet H, Champion G, Bertheleme JP, Niaudet P, McDonald F, Hildebrandt F, Johnson CA, Vekemans M, Antignac C, Ruther U, Schneider-Maunoury S, Attie-Bitach T, Saunier S (2007) The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat Genet 39:875–881PubMedCrossRefGoogle Scholar
  15. 15.
    Dixon-Salazar T, Silhavy JL, Marsh SE et al (2004) Mutations in the AHI1 gene, encoding Jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 75:979–987PubMedCrossRefGoogle Scholar
  16. 16.
    Doherty D (2009) Joubert syndrome: insights into brain development, cilium biology, and complex disease. Semin Pediatr Neurol 16:143–154PubMedCrossRefGoogle Scholar
  17. 17.
    Doherty D, Glass IA, Siebert JR, Strouse PJ, Parisi MA, Shaw DW, Chance PF, Barr M Jr, Nyberg D (2005) Prenatal diagnosis in pregnancies at risk for Joubert syndrome by ultrasound and MRI. Prenat Diagn 25:442–447PubMedCrossRefGoogle Scholar
  18. 18.
    Doherty D, Parisi MA, Finn LS, Gunay-Aygun M, Al-Mateen M, Bates D, Clericuzio C, Demir H, Dorschner M, van Essen AJ, Gahl WA, Gentile M, Gorden NT, Hikida A, Knutzen D, Ozyurek H, Phelps I, Rosenthal P, Verloes A, Weigand H, Chance PF, Dobyns WB, Glass IA (2010) Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J Med Genet 47:8–21PubMedCrossRefGoogle Scholar
  19. 19.
    Eggenschwiler JT, Anderson KV (2007) Cilia and developmental signaling. Annu Rev Cell Dev Biol 23:345–373PubMedCrossRefGoogle Scholar
  20. 20.
    Exome Variant Server (2011) NHLBI Exome Sequencing Project (ESP), Seattle, WA. URL: Accessed Sept. 2011
  21. 21.
    Ferrante MI, Zullo A, Barra A, Bimonte S, Messaddeq N, Studer M, Dolle P, Franco B (2006) Oral-facial-digital type I protein is required for primary cilia formation and left–right axis specification. Nat Genet 38:112–117PubMedCrossRefGoogle Scholar
  22. 22.
    Fluss J, Blaser S, Chitayat D, Akoury H, Glanc P, Skidmore M, Raybaud C (2006) Molar tooth sign in fetal brain magnetic resonance imaging leading to the prenatal diagnosis of Joubert syndrome and related disorders. J Child Neurol 21:320–324PubMedCrossRefGoogle Scholar
  23. 23.
    Friede RL, Boltshauser E (1978) Uncommon syndromes of cerebellar vermis aplasia. I: Joubert syndrome. Dev Med Child Neurol 20:758–763PubMedCrossRefGoogle Scholar
  24. 24.
    Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ, García-Verdugo JM, Katsanis N, Hildebrandt F, Reiter JF (2011) A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 43:776–784PubMedCrossRefGoogle Scholar
  25. 25.
    Giordano L, Vignoli A, Pinelli L, Brancati F, Accorsi P, Faravelli F, Gasparotti R, Granata T, Giaccone G, Inverardi F, Frassoni C, Dallapiccola B, Valente EM, Spreafico R (2009) Joubert syndrome with bilateral polymicrogyria: clinical and neuropathological findings in two brothers. Am J Med Genet A 149A:1511–1515PubMedCrossRefGoogle Scholar
  26. 26.
    Gorden NT, Arts HH, Parisi MA, Coene KL, Letteboer SJ, van Beersum SE, Mans DA, Hikida A, Eckert M, Knutzen D, Alswaid AF, Ozyurek H, Dibooglu S, Otto EA, Liu Y, Davis EE, Hutter CM, Bammler TK, Farin FM, Dorschner M, Topcu M, Zackai EH, Rosenthal P, Owens KN, Katsanis N, Vincent JB, Hildebrandt F, Rubel EW, Raible DW, Knoers NV, Chance PF, Roepman R, Moens CB, Glass IA, Doherty D (2008) CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am J Hum Genet 83:559–571PubMedCrossRefGoogle Scholar
  27. 27.
    Goodship J, Platt J, Smith R et al (1991) A male with type I orofaciodigital syndrome. J Med Genet 28:691–694PubMedCrossRefGoogle Scholar
  28. 28.
    Harting I, Kotzaeridou U, Poretti A, Seitz A, Pietz J, Bendszus M, Boltshauser E (2011) Interpeduncular heterotopia in Joubert syndrome: a previously undescribed MR finding. AJNR Am J Neuroradiol 32:1286–1289PubMedCrossRefGoogle Scholar
  29. 29.
    Han YG, Spassky N, Romaguera-Ros M et al (2008) Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat Neurosci 11:277–284PubMedCrossRefGoogle Scholar
  30. 30.
    Heninger E, Otto E, Imm A, Caridi G, Hildebrandt F (2001) Improved strategy for molecular genetic diagnostics in juvenile nephronophthisis. Am J Kidney Dis 37:1131–1139PubMedCrossRefGoogle Scholar
  31. 31.
    Ishikawa T, Zhu BL, Li DR, Zhao D, Michiue T, Maeda H (2008) An autopsy case of an infant with Joubert syndrome who died unexpectedly and a review of the literature. Forensic Sci Int 179:e67–e73PubMedCrossRefGoogle Scholar
  32. 32.
    Ivarsson SA, Bjerre I, Brun A, Ljungberg O, Maly E, Taylor I (1993) Joubert syndrome associated with Leber amaurosis and multicystic kidneys. Am J Med Genet 45:542–547PubMedCrossRefGoogle Scholar
  33. 33.
    Joubert M, Eisenring JJ, Robb JP, Andermann F (1969) Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 19:813–825PubMedGoogle Scholar
  34. 34.
    Koirala S, Jin Z, Piao X, Corfas G (2009) GPR56-regulated granule cell adhesion is essential for rostral cerebellar development. J Neurosci 29:7439–7449PubMedCrossRefGoogle Scholar
  35. 35.
    Kumandas S, Akcakus M, Coskun A, Gumus H (2004) Joubert syndrome: review and report of seven new cases. Eur J Neurol 11:505–510PubMedCrossRefGoogle Scholar
  36. 36.
    Lancaster MA, Gopal DJ, Kim J, Saleem SN, Silhavy JL, Louie CM, Thacker BE, Williams Y, Zaki MS, Gleeson JG (2011) Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. Nat Med 17:726–731PubMedCrossRefGoogle Scholar
  37. 37.
    Liu JS (2011) Molecular genetics of neuronal migration disorders. Curr Neurol Neurosci Rep 11(2):171–178PubMedCrossRefGoogle Scholar
  38. 38.
    Lopes CA, Prosser SL, Romio L, Hirst RA, O’Callaghan C, Woolf AS, Fry AM (2011) Centriolar satellites are assembly points for proteins implicated in human ciliopathies, including oral-facial-digital syndrome 1. J Cell Sci 124:600–612PubMedCrossRefGoogle Scholar
  39. 39.
    Maria BL, Quisling RG, Rosainz LC, Yachnis AT, Gitten J, Dede D, Fennell E (1999) Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic significance. J Child Neurol 14:368–376PubMedCrossRefGoogle Scholar
  40. 40.
    McGraw P (2003) The molar tooth sign. Radiology 229:671–672PubMedCrossRefGoogle Scholar
  41. 41.
    Millen KJ, Gleeson JG (2008) Cerebellar development and disease. Curr Opin Neurobiol 18:12–19PubMedCrossRefGoogle Scholar
  42. 42.
    Ocbina PJR, Anderson KV (2008) Intraflagellar transport, cilia and mammalian Hedgehog signaling: analysis in mouse embryonic fibroblasts. Dev Dyn 237:2030–2038PubMedCrossRefGoogle Scholar
  43. 43.
    Padgett KR, Maria BL, Yachnis AT, Blackband SJ (2002) Ex vivo high-resolution magnetic resonance imaging of the brain in Joubert’s syndrome. J Child Neurol 17:911–913PubMedCrossRefGoogle Scholar
  44. 44.
    Parisi MA, Dobyns WB (2003) Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab 80:36–53PubMedCrossRefGoogle Scholar
  45. 45.
    Parisi MA, Doherty D, Chance PF, Glass IA (2007) Joubert syndrome (and related disorders) (OMIM 213300). Eur J Hum Genet 15:511–521PubMedCrossRefGoogle Scholar
  46. 46.
    Poretti A, Brehmer U, Scheer I et al (2008) Prenatal and neonatal MR imaging findings in oral-facial-digital syndrome type VI. AJNR 29:1090–1091PubMedCrossRefGoogle Scholar
  47. 47.
    Poretti A, Huisman TA, Scheer I, Boltshauser E (2011) Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol 32:1459–1463PubMedCrossRefGoogle Scholar
  48. 48.
    Prattichizzo C, Macca M, Novelli V, Giorgio G, Barra A, Franco B, Oral-Facial-Digital Type ICG (2008) Mutational spectrum of the oral-facial-digital type I syndrome: a study on a large collection of patients. Hum Mutat 29:1237–1246PubMedCrossRefGoogle Scholar
  49. 49.
    Putoux A, Thomas S, Coene KL, Davis EE, Alanay Y, Ogur G, Uz E, Buzas D, Gomes C, Patrier S, Bennett CL, Elkhartoufi N, Frison MH, Rigonnot L, Joyé N, Pruvost S, Utine GE, Boduroglu K, Nitschke P, Fertitta L, Thauvin-Robinet C, Munnich A, Cormier-Daire V, Hennekam R, Colin E, Akarsu NA, Bole-Feysot C, Cagnard N, Schmitt A, Goudin N, Lyonnet S, Encha-Razavi F, Siffroi JP, Winey M, Katsanis N, Gonzales M, Vekemans M, Beales PL, Attié-Bitach T (2011) KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet 43:601–606PubMedCrossRefGoogle Scholar
  50. 50.
    Quisling RG, Barkovich AJ, Maria BL (1999) Magnetic resonance imaging features and classification of central nervous system malformations in Joubert syndrome. J Child Neurol 14:628–635 (discussion 669–672)PubMedCrossRefGoogle Scholar
  51. 51.
    Ribes V, Stutzmann F, Bianchetti L, Guillemot F, Dolle P, Le Roux I (2008) Combinatorial signaling controls Neurogenin2 expression at the onset of spinal neurogenesis. Dev Biol 321:470–481PubMedCrossRefGoogle Scholar
  52. 52.
    Romano S, Boddaert N, Desguerre I, Hubert L, Salomon R, Seidenwurm D, Bahi-Buisson N, Nabbout R, Sonigo P, Lyonnet S, Brunelle F, Munnich A, de Lonlay P (2006) Molar tooth sign and superior vermian dysplasia: a radiological, clinical, and genetic study. Neuropediatrics 37:42–45PubMedCrossRefGoogle Scholar
  53. 53.
    Saleem SN, Zaki MS (2010) Role of MR imaging in prenatal diagnosis of pregnancies at risk for Joubert syndrome and related cerebellar disorders. AJNR Am J Neuroradiol 31:424–429PubMedCrossRefGoogle Scholar
  54. 54.
    Saleem SN, Zaki MS, Soliman NA, Momtaz M (2011) Prenatal magnetic resonance imaging diagnosis of molar tooth sign at 17 to 18 weeks of gestation in two fetuses at risk for Joubert syndrome and related cerebellar disorders. Neuropediatrics 42:35–38PubMedCrossRefGoogle Scholar
  55. 55.
    Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA, Baye LM, Wen X, Scales SJ, Kwong M, Huntzicker EG, Sfakianos MK, Sandoval W, Bazan JF, Kulkarni P, Garcia-Gonzalo FR, Seol AD, O’Toole JF, Held S, Reutter HM, Lane WS, Rafiq MA, Noor A, Ansar M, Devi AR, Sheffield VC, Slusarski DC, Vincent JB, Doherty DA, Hildebrandt F, Reiter JF, Jackson PK (2011) Mapping the NPHP–JBTS–MKS protein network reveals ciliopathy disease genes and pathways. Cell 145:513–528PubMedCrossRefGoogle Scholar
  56. 56.
    Saraiva JM, Baraitser M (1992) Joubert syndrome: a review. Am J Med Genet 43:726–731PubMedCrossRefGoogle Scholar
  57. 57.
    Sattar S, Gleeson JG (2011) The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders. Dev Med Child Neurol 53:793–798PubMedCrossRefGoogle Scholar
  58. 58.
    Sawamoto K, Wichterie H, Gonzalez-Perez O et al (2006) New neurons follow the flow of cerebrospinal fluid in the adult brain. Science 311:629–632PubMedCrossRefGoogle Scholar
  59. 59.
    Schneider L, Cammer M, Lehman J et al (2010) Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts. Cell Physiol Biochem 25:279–292PubMedCrossRefGoogle Scholar
  60. 60.
    Senocak EU, Oguz KK, Haliloglu G, Topcu M, Cila A (2010) Structural abnormalities of the brain other than molar tooth sign in Joubert syndrome-related disorders. Diagn Interv Radiol 16:3–6PubMedGoogle Scholar
  61. 61.
    Singla V, Romaguera-Ros M, Garcia-Verdugo JM, Reiter JF (2010) Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Dev Cell 18:410–424PubMedCrossRefGoogle Scholar
  62. 62.
    Spassky N, Han YG, Aguilar A, Strehl L, Besse L, Laclef C, Ros MR, Garcia-Verdugo JM, Alvarez-Buylla A (2008) Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev Biol 317:246–259PubMedCrossRefGoogle Scholar
  63. 63.
    Sztriha L, Al-Gazali LI, Aithala GR, Nork M (1999) Joubert’s syndrome: new cases and review of clinicopathologic correlation. Pediatr Neurol 20:274–281PubMedCrossRefGoogle Scholar
  64. 64.
    ten Donkelaar HJ, Hoevenaars F, Wesseling P (2000) A case of Joubert’s syndrome with extensive cerebral malformations. Clin Neuropathol 19:85–93PubMedGoogle Scholar
  65. 65.
    ten Donkelaar HJ, Lammens M (2009) Development of the human cerebellum and its disorders. Clin Perinatol 36:513–530PubMedCrossRefGoogle Scholar
  66. 66.
    Valente EM, Logan CV, Mougou-Zerelli S, Lee JH, Silhavy JL, Brancati F, Iannicelli M, Travaglini L, Romani S, Illi B, Adams M, Szymanska K, Mazzotta A, Lee JE, Tolentino JC, Swistun D, Salpietro CD, Fede C, Gabriel S, Russ C, Cibulskis K, Sougnez C, Hildebrandt F, Otto EA, Held S, Diplas BH, Davis EE, Mikula M, Strom CM, Ben-Zeev B, Lev D, Sagie TL, Michelson M, Yaron Y, Krause A, Boltshauser E, Elkhartoufi N, Roume J, Shalev S, Munnich A, Saunier S, Inglehearn C, Saad A, Alkindy A, Thomas S, Vekemans M, Dallapiccola B, Katsanis N, Johnson CA, Attie-Bitach T, Gleeson JG (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 42:619–625PubMedCrossRefGoogle Scholar
  67. 67.
    van Dorp DB, Palan A, Kwee ML, Barth PG, van der Harten JJ (1991) Joubert syndrome: a clinical and pathological description of an affected male and a female fetus from the same sibship. Am J Med Genet 40:100–104PubMedCrossRefGoogle Scholar
  68. 68.
    Watanabe H, Murakami F (2009) Real time analysis of pontine neurons during initial stages of nucleogenesis. Neurosci Res 64:20–29PubMedCrossRefGoogle Scholar
  69. 69.
    Yachnis AT, Rorke LB (1999) Neuropathology of Joubert syndrome. J Child Neurol 14:655–659 (discussion 669–672)PubMedCrossRefGoogle Scholar
  70. 70.
    Yu W, McDonnell K, Taketo MM, Bai CB (2008) Wnt signaling determines ventral spinal cord cell fates in a time-dependent manner. Development 135:3687–3696PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of Neurological SurgerySeattle Children’s Research Institute, University of WashingtonSeattleUSA
  2. 2.Department of PediatricsSeattle Children’s Research Institute, University of WashingtonSeattleUSA

Personalised recommendations