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

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.

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