P57(Kip2) Cooperates with Nurr1 in Developing Dopamine Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 Dec 13

PMID 14671317

Citations 60

Authors

Bertrand Joseph

Asa Wallen-Mackenzie

Gerard Benoit

Takashi Murata

Eliza Joodmardi

Sam Okret

Thomas Perlmann

Affiliations

Soon will be listed here.

Abstract

Cyclin-dependent kinase inhibitors of the Cip/Kip family play critical roles in regulating cell proliferation during embryogenesis. However, these proteins also influence cell differentiation by mechanisms that have remained unknown. Here we show that p57Kip2 is expressed in postmitotic differentiating midbrain dopamine cells. Induction of p57Kip2 expression depends on Nurr1, an orphan nuclear receptor that is essential for dopamine neuron development. Moreover, analyses of p57Kip2 gene-targeted mice revealed that p57Kip2 is required for the maturation of midbrain dopamine neuronal cells. Additional experiments in a dopaminergic cell line demonstrated that p57Kip2 can promote maturation by a mechanism that does not require p57Kip2-mediated inhibition of cyclin-dependent kinases. Instead, evidence indicates that p57Kip2 functions by a direct protein-protein interaction with Nurr1. Thus, in addition to its established function in control of proliferation, these results reveal a mechanism whereby p57Kip2 influences postmitotic differentiation of dopamine neurons.

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