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First published online 30 August 2006
doi: 10.1242/dev.02556

Development 133, 3929-3937 (2006)
Published by The Company of Biologists 2006
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Loss of cyclin D1 impairs cerebellar development and suppresses medulloblastoma formation

Jennifer Pogoriler1, Kathleen Millen2, Manuel Utset3 and Wei Du1,*

1 Ben May Institute for Cancer Research, The University of Chicago, 924 E. 57th Street, Chicago, IL 60637, USA.
2 Department of Human Genetics, The University of Chicago, 924 E. 57th Street, Chicago, IL 60637, USA.
3 Department of Pathology, The University of Chicago, 924 E. 57th Street, Chicago, IL 60637, USA.

* Author for correspondence (e-mail: wdu{at}huggins.bsd.uchicago.edu)

Accepted 31 July 2006

Medulloblastoma, the most common malignant brain tumor of childhood, is believed to derive from immature granule neuron precursors (GNPs) that normally proliferate in the external granule layer before exiting the cell cycle and migrating to their mature location in the inner granule layer. In this study, we examined the expression of D type cyclins in GNPs during cerebellar development and showed that GNPs in early development expressed only cyclin D1, whereas later GNPs expressed both cyclins D1 and D2. Coinciding with the period of cyclin D1-only expression, Ccnd1-/- mice showed reduced proliferation of GNPs and impaired growth of the cerebellum. Interestingly, removal of cyclin D1 was sufficient to drastically reduce the incidence of medulloblastoma in Ptch1+/- mice, despite the fact that these tumors showed upregulation of both cyclins D1 and D2. We showed that cyclin D1 has an earlier role in tumorigenesis: in the absence of cyclin D1, the incidence and overall volume of `preneoplastic' lesions were significantly decreased. We propose a model that links a role of cyclin D1 in normal GNP proliferation with its early role in tumorigenesis.

Key words: Cyclin D1, Cerebellar development, Medulloblastoma, Ptch1, Mouse


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