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Molecular and Cellular Biology, June 2005, p. 5134-5145, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5134-5145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

High-Level Activation of Cyclic AMP Signaling Attenuates Bone Morphogenetic Protein 2-Induced Sympathoadrenal Lineage Development and Promotes Melanogenesis in Neural Crest Cultures

Ming Ji and Ourania M. Andrisani*

Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana

Received 13 September 2004/ Returned for modification 24 November 2004/ Accepted 16 March 2005

The intensity of cyclic AMP (cAMP) signaling is a differential instructive signal in neural crest (NC) cell specification. By an unknown mechanism, sympathoadrenal lineage specification is suppressed by high-level activation of cAMP signaling. In NC cultures, high-level activation of cAMP signaling mediates protein kinase A (PKA)-dependent Rap1-B-Raf-ERK1/2 activation, leading to cytoplasmic accumulation of phospho-Smad1, thus terminating bone morphogenetic protein 2 (BMP2)-induced sympathoadrenal cell development. Concurrently, cAMP signaling induces transcription of the melanocyte-determining transcription factor Mitf and melanogenesis. dnACREB and E1A inhibit Mitf expression and melanogenesis, supporting the notion that CREB activation is necessary for melanogenesis. However, constitutively active CREBDIEDML without PKA activation is insufficient for Mitf expression and melanogenesis, indicating PKA regulates additional aspects of Mitf transcription. Thus, high-level activation of cAMP signaling plays a dual role in NC cell differentiation: attenuation of BMP2-induced sympathoadrenal cell development and induction of melanogenesis. We conclude the intensity of activation of signal transduction cascades determines cell lineage segregation mechanisms.

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

Molecular and Cellular Biology, June 2005, p. 5134-5145, Vol. 25, No. 12
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.12.5134-5145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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