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N-Myc and the cyclin-dependent kinase inhibitors p18Ink4c and p27Kip1 coordinately regulate cerebellar development.

Zindy, Frederique and Knoepfler, Paul S and Xie, Suqing and Sherr, Charles J and Eisenman, Robert N and Roussel, Martine F (2006) N-Myc and the cyclin-dependent kinase inhibitors p18Ink4c and p27Kip1 coordinately regulate cerebellar development. Proceedings of the National Academy of Sciences of the United States of America, 103 (31). pp. 11579-11583. ISSN 0027-8424

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Conditional N-Myc deletion limits the proliferation of granule neuron progenitors (GNPs), perturbs foliation, and leads to reduced cerebellar mass. We show that c-Myc mRNA levels increase in N-Myc-null GNPs and that simultaneous deletion of both c- and N-Myc exacerbates defective cerebellar development. Moreover, N-Myc loss has been shown to trigger the precocious expression of two cyclin-dependent kinase inhibitors, Kip1 and Ink4c, in the cerebellar primordium. We now further demonstrate that the engineered disruption of the Kip1 and Ink4c genes in N-Myc-null cerebella partially rescues GNP cell proliferation and cerebellar foliation. These results provide definitive genetic evidence that expression of N-Myc and concomitant down-regulation of Ink4c and Kip1 contribute to the proper development of the cerebellum.

Item Type: Article
Additional Information: This article is freely available in PubMed Central and at the journal's website.
DOI: 10.1073/pnas.0604727103
PubMed ID: 16864777
PMCID: PMC1518798
Grant Numbers: CA-96832, CA-72907, CA-20525, K01-CA-114400, CA-21765
Keywords or MeSH Headings: Animals; Cell Proliferation; Cerebellum/anatomy & histology/embryology/growth & development; Cyclin-Dependent Kinase Inhibitor p18/genetics/metabolism; Cyclin-Dependent Kinase Inhibitor p27/genetics/metabolism; Gene Expression Regulation, Developmental; Mice; Mice, Knockout; Mice, Transgenic; Proto-Oncogene Proteins c-myc/genetics/metabolism;
Subjects: Cellular and Organismal Processes > Development
Molecules > Proteins
Molecules > Genes > Oncogenes
Depositing User: Library Staff
Date Deposited: 10 Dec 2008 23:54
Last Modified: 10 May 2010 21:59

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