Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool

Viktor Chizhikov, James Davenport, Qihong Zhang, Evelyn Kim Shih, Olga A. Cabello, Jannon L. Fuchs, Bradley K. Yoder, Kathleen J. Millen

Research output: Contribution to journalArticle

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Abstract

Although human congenital cerebellar malformations are common, their molecular and developmental basis is still poorly understood. Recently, cilia-related gene deficiencies have been implicated in several congenital disorders that exhibit cerebellar abnormalities such as Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, and Orofaciodigital syndrome. The association of cilia gene mutations with these syndromes suggests that cilia may be important for cerebellar development, but the nature of cilia involvement has not been elucidated. To assess the importance of cilia-related proteins during cerebellar development, we studied the effects of CNS-specific inactivation of two mouse genes whose protein products are critical for cilia formation and maintenance, IFT88, (also known as polaris or Tg737), which encodes intraflagellar transport 88 homolog, and Kif3a, which encodes kinesin family member 3a. We showed that loss of either of these genes caused severe cerebellar hypoplasia and foliation abnormalities, primarily attributable to a failure of expansion of the neonatal granule cell progenitor population. In addition, granule cell progenitor proliferation was sensitive to partial loss of IFT function in a hypomorphic mutant of IFT88 (IFT88orpk), an effect that was modified by genetic background. IFT88 and Kif3a were not required for the specification and differentiation of most other cerebellar cell types, including Purkinje cells. Together, our observations constitute the first demonstration that cilia proteins are essential for normal cerebellar development and suggest that granule cell proliferation defects may be central to the cerebellar pathology in human cilia-related disorders.

Original languageEnglish (US)
Pages (from-to)9780-9789
Number of pages10
JournalJournal of Neuroscience
Volume27
Issue number36
DOIs
StatePublished - Sep 5 2007

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Cilia
Morphogenesis
Proteins
Orofaciodigital Syndromes
Bardet-Biedl Syndrome
Cell Proliferation
Genes
Kinesin
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Purkinje Cells
Stem Cells
Maintenance
Pathology
Mutation

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. / Chizhikov, Viktor; Davenport, James; Zhang, Qihong; Shih, Evelyn Kim; Cabello, Olga A.; Fuchs, Jannon L.; Yoder, Bradley K.; Millen, Kathleen J.

In: Journal of Neuroscience, Vol. 27, No. 36, 05.09.2007, p. 9780-9789.

Research output: Contribution to journalArticle

Chizhikov, V, Davenport, J, Zhang, Q, Shih, EK, Cabello, OA, Fuchs, JL, Yoder, BK & Millen, KJ 2007, 'Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool', Journal of Neuroscience, vol. 27, no. 36, pp. 9780-9789. https://doi.org/10.1523/JNEUROSCI.5586-06.2007
Chizhikov, Viktor ; Davenport, James ; Zhang, Qihong ; Shih, Evelyn Kim ; Cabello, Olga A. ; Fuchs, Jannon L. ; Yoder, Bradley K. ; Millen, Kathleen J. / Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. In: Journal of Neuroscience. 2007 ; Vol. 27, No. 36. pp. 9780-9789.
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