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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 p27Kip1 Transcription, Coordinating Neural Progenitor Cell Cycle Exit and Differentiation{triangledown} ,{dagger}

Maryline Paris,1 Wen-Horng Wang,1 Min-Hwa Shin,1 David S. Franklin,2 and Ourania M. Andrisani1*

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 p27Kip1 is transcriptionally induced, switching specific neural progenitors from proliferation to differentiation. However, neuronal differentiation-specific transcription factors mediating p27Kip1 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 p27Kip1 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 p27Kip1 transcription, G1 arrest, and neuronal differentiation. Small interfering RNA silencing of either Phox2a or p27Kip1 suppresses p27Kip1 transcription and neuronal differentiation, suggesting a causal link between p27Kip1 expression and differentiation. Conversely, ectopic Phox2a expression via the Tet-off expression system promotes accelerated CAD cell neuronal differentiation and p27Kip1 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 p27Kip1 promoter in vivo and mediates p27Kip1-luciferase expression in CAD and NC cells. We conclude that developmental cues of cAMP signaling causally link Phox2a activation with p27Kip1 transcription, thereby coordinating neural progenitor cell cycle exit and differentiation.

* Corresponding author. Mailing address: Department of Basic Medical Sciences, Purdue University, 625 Harrison Street, West Lafayette, IN 47907-2026. Phone: (765) 494-8131. Fax: (765) 494-0781. E-mail: andrisao{at}purdue.edu.

{triangledown} Published ahead of print on 18 September 2006.

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

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.



This article has been cited by other articles:

  • Shin, M. H., Mavila, N., Wang, W.-H., Vega Alvarez, S., Hall, M. C., Andrisani, O. M. (2009). Time-Dependent Activation of Phox2a by the Cyclic AMP Pathway Modulates Onset and Duration of p27Kip1 Transcription. Mol. Cell. Biol. 29: 4878-4890 [Abstract] [Full Text]  
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