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Molecular and Cellular Biology, September 2005, p. 7645-7656, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7645-7656.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

FoxO1a-Cyclic GMP-Dependent Kinase I Interactions Orchestrate Myoblast Fusion

Philippe R. J. Bois,1,2 Vanessa F. Brochard,2 Adèle V. A. Salin-Cantegrel,2 John L. Cleveland,1 and Gerard C. Grosveld2*

Departments of Biochemistry,1 Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee 381052

Received 12 November 2004/ Returned for modification 16 January 2005/ Accepted 6 June 2005

The regulatory circuits that orchestrate mammalian myoblast cell fusion during myogenesis are poorly understood. The transcriptional activity of FoxO1a directly regulates this process, yet the molecular mechanisms governing FoxO1a activity during muscle cell differentiation remain unknown. Here we show an autoregulatory loop in which FoxO1a directly activates transcription of the cyclic GMP-dependent protein kinase I (cGKI) gene and where the ensuing cGKI activity phosphorylates FoxO1a and abolishes its DNA binding activity. These findings establish the FoxO1a-to-cGKI pathway as a novel feedback loop that allows the precise tuning of myoblast fusion. Interestingly, this pathway appears to operate independently of muscle cell differentiation programs directed by myogenic transcription factors.

* Corresponding author. Mailing address: Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105. Phone: (901) 495-2279. Fax: (901) 526-2907. E-mail: gerard.grosveld{at}stjude.org.

Molecular and Cellular Biology, September 2005, p. 7645-7656, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7645-7656.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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