p57Kip2 cooperates with Nurr1 in developing dopamine cells

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 p57(Kip2) is expressed in postmitotic differentiating midbrain dopamine cells. Induction of p57(Kip2) expression depends on Nurr1, an orphan nuclear receptor that is essential for dopamine neuron development. Moreover, analyses of p57(Kip2) gene-targeted mice revealed that p57(Kip2) is required for the maturation of midbrain dopamine neuronal cells. Additional experiments in a dopaminergic cell line demonstrated that p57(Kip2) can promote maturation by a mechanism that does not require p57(Kip2)-mediated inhibition of cyclin-dependent kinases. Instead, evidence indicates that p57(Kip2) 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 p57(Kip2) influences postmitotic differentiation of dopamine neurons.