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Molecular and Cellular Biology, December 2006, p. 8826-8839, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00575-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Homeodomain Transcription Factor Phox2a, via Cyclic AMP-Mediated Activation, Induces p27^Kip1 Transcription, Coordinating Neural Progenitor Cell Cycle Exit and Differentiation ^,

Department of Basic Medical Sciences,¹ Biological Sciences Department, Purdue University, West Lafayette, Indiana 47907²

Received 1 April 2006/ Returned for modification 2 August 2006/ Accepted 1 September 2006

Mechanisms coordinating neural progenitor cell cycle exit and differentiation are incompletely understood. The cyclin-dependent kinase inhibitor p27^Kip1 is transcriptionally induced, switching specific neural progenitors from proliferation to differentiation. However, neuronal differentiation-specific transcription factors mediating p27^Kip1 transcription have not been identified. We demonstrate the homeodomain transcription factor Phox2a, required for central nervous system (CNS)- and neural crest (NC)-derived noradrenergic neuron differentiation, coordinates cell cycle exit and differentiation by inducing p27^Kip1 transcription. Phox2a transcription and activation in the CNS-derived CAD cell line and primary NC cells is mediated by combined cyclic AMP (cAMP) and bone morphogenetic protein 2 (BMP2) signaling. In the CAD cellular model, cAMP and BMP2 signaling initially induces proliferation of the undifferentiated precursors, followed by p27^Kip1 transcription, G₁ arrest, and neuronal differentiation. Small interfering RNA silencing of either Phox2a or p27^Kip1 suppresses p27^Kip1 transcription and neuronal differentiation, suggesting a causal link between p27^Kip1 expression and differentiation. Conversely, ectopic Phox2a expression via the Tet-off expression system promotes accelerated CAD cell neuronal differentiation and p27^Kip1 transcription only in the presence of cAMP signaling. Importantly, endogenous or ectopically expressed Phox2a activated by cAMP signaling binds homeodomain cis-acting elements of the p27^Kip1 promoter in vivo and mediates p27^Kip1-luciferase expression in CAD and NC cells. We conclude that developmental cues of cAMP signaling causally link Phox2a activation with p27^Kip1 transcription, thereby coordinating neural progenitor cell cycle exit and differentiation.

Published ahead of print on 18 September 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

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