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First published online 7 August 2007
doi: 10.1242/jcs.006619

Journal of Cell Science 120, 3086-3098 (2007)
Published by The Company of Biologists 2007
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Research Article

The RhoA effector mDiaphanous regulates MyoD expression and cell cycle progression via SRF-dependent and SRF-independent pathways

Suchitra Devi Gopinath1, Shuh Narumiya2 and Jyotsna Dhawan1,*

1 Center for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India
2 Department of Pharmacology, Kyoto University, Kyoto, Japan

* Author for correspondence (e-mail: jdhawan{at}ccmb.res.in)

Accepted 25 June 2007

Expression of the key muscle transcription factor MyoD is regulated by RhoA GTPase, which is an important regulator of adhesion-dependent signaling. We show that mDiaphanous (mDia) – an adaptor protein that mediates the effects of RhoA on cell motility and the cytoskeleton – is an upstream regulator of MyoD in C2C12 mouse myoblasts. Knockdown of mDia1 reduced MyoD expression and proliferation via a serum-response factor (SRF)-dependent pathway. Surprisingly, overexpression of a Rho-independent form of mDia1 (mDia{Delta}N3), despite activating SRF, also suppressed MyoD and the cell cycle, suggesting the presence of a second pathway downstream of mDia1. We present evidence that the alternative pathway by which mDia1 regulates MyoD involves T-cell factor (TCF)/lymphoid enhancer factor (LEF) and its co-activator, beta-catenin. TCF activity was suppressed by mDia{Delta}N3 and induced by silencing mDia. mDia{Delta}N3 disrupted the signal-dependent nuclear localization of beta-catenin and suppressed MyoD expression. Co-expression of a degradation-resistant form of beta-catenin with mDia{Delta}N3 restored MyoD expression, suggesting a mechanistic link between the two signaling proteins. We also implicate a region encompassing the FH1 domain of mDia1 in beta-catenin-TCF regulation. Taken together, our results suggest that a balance between two pathways downstream of mDia regulates MyoD expression and cell cycle progression.

Key words: mDia1, MyoD, SRF, RhoA, Adhesion-dependent signaling, Quiescence, Synchronized myoblasts, beta-catenin, TCF, APC


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