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

Frederique Zindy, Paul S Knoepfler, Suqing Xie, Charles J. Sherr, Robert N. Eisenman, Martine F. Roussel

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11579-11583
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number31
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

Keywords

  • Cell cycle inhibitor
  • Cerebellum
  • Granule neuron progenitor
  • Myc
  • N-Myc deficiency

ASJC Scopus subject areas

  • Genetics
  • General

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