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The Journal of Neuroscience, September 5, 2007, 27(36):9780-9789; doi:10.1523/JNEUROSCI.5586-06.2007

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Neurobiology of Disease
Cilia Proteins Control Cerebellar Morphogenesis by Promoting Expansion of the Granule Progenitor Pool

Victor V. Chizhikov,^1 * James Davenport,^3 * Qihong Zhang,⁴ Evelyn Kim Shih,² Olga A. Cabello,⁵ Jannon L. Fuchs,⁶ Bradley K. Yoder,³ and Kathleen J. Millen¹

¹Department of Human Genetics and ²Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637, ³Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, ⁴Department of Pediatrics, Division of Medical Genetics, University of Iowa, Iowa City, Iowa 52242, ⁵Department of Biochemistry and Molecular Biology, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614, and ⁶Department of Biological Sciences, University of North Texas, Denton, Texas 76203

Correspondence should be addressed to Kathleen J. Millen, 920 East 58th Street, Cummings Life Sciences Center 319, Chicago, IL 60637. Email: kmillen{at}genetics.bsd.uchicago.edu

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 (IFT88^orpk), 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.

Key words: cilia; cerebellum; cerebellar hypoplasia; Joubert syndrome; Shh; granule neuron progenitors

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Received Dec. 22, 2006; revised July 12, 2007; accepted July 13, 2007.

Correspondence should be addressed to Kathleen J. Millen, 920 East 58th Street, Cummings Life Sciences Center 319, Chicago, IL 60637. Email: kmillen{at}genetics.bsd.uchicago.edu

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