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    In vivo analysis of the Serum Response factor (SRF) function in the ontogenesis and maintenance of skeletal and cardiac muscles

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    Principal investigators : Dominique DAEGELEN and David TUIL

     

    SRF is at the confluence of multiple signalling pathways controlling the transcription of immediate early response genes to serum and muscle specific genes. An increasing body of data, including those obtained in the team, underline the crucial role that SRF could play in myogenesis and muscle physiology. Alterations of SRF function could be involved in some muscle pathologies and, in particular, in heart failure.

     

    Our objective is to evaluate the role of SRF both in the establishment and maintenance of the cardiac and skeletal muscle lineages. For this purpose we are developing different mouse models of SRF conditional gene inactivation, using the Cre/loxP system.

     

    In collaboration with Dr Zhenlin Li’s team (CNRS UMR 7079, Jussieu) we could thus demonstrate that SRF is crucial for cardiac differentiation and maturation in the embryo (Parlakian, Tuil et al, Mol Cell Biol, 1994, (24) 12: 5281-9) and for cardiac function in the adult (Parlakian, Charvet et al, Circulation. 2005,112(19): 2930-9). Within two months following the induction of SRF loss in the heart, adult mutant mice developed a dilated cardiomyopathy and cardiac failure. Our results also reinforce the emerging notion that SRF could be one of the main downstream effectors of pathways leading to cardiac hypertrophy. Since it is possible to trigger at will depletion of SRF in cardiomyocytes, this mutant mice model is now used to study progression towards dilated cadiomyopathy, heart failure and to decipher the chain of events and signalling pathways leading to this phenotype. Owing to its characteristics, this inducible mouse model of cardiomyopthy will be also helpful for evaluating therapeutic strategies aiming to stop or slow down progression towards heart failure.

     

    We are also investigating SRF function in skeletal muscles growth and hypertrophy. To address this question we are developing different mutant mice models with a constitutive or inducible myofiber-targeted disruption of the SRF gene. Our present results show that SRF is crucial for skeletal muscle growth, maturation and regeneration. The signalling pathways in which SRF could be involved as a downstream transcriptional effectors are under study.