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We have recently identified the transcriptional co-factor Yap, a key member of the Hippo pathway, as a novel regulator of myogenesis (Watt et al. 2010). Moreover, Yap expression increases greatly when satellite cells (i.e. muscle stem cells) progress from quiescence to activation and we have now obtained evidence that Yap regulates key fate decisions of these cells. The first aim is to overexpress GFP-tagged Yap and Taz (a closely related paralogue of Yap) constructs in C2C12 and satellite cells. The tagged Yap and Taz will then be monitored and modifications will be analysed when these cells make fate decisions using live cell imaging among other. Yap and Taz have also been shown to sense mechanical stress and to regulate cell fate in mesenchymal stem cells via the cytoskeleton (Dupont et al. 2011). As satellite cells respond to mechanical muscle loading (e.g. resistance or strength training) the second aim is test the hypothesis that Yap and/or Taz sense mechanical loading via the cytoskeleton or dystrophin-dystroglycan (which have WW and proline-rich domains that are common in the Hippo pathway) and regulate the activation, proliferation and differentiation of satellite cells accordingly. This project will run in parallel to a well supported MRC funded project which involves transgenic animals and a Yap ChIP-Seq experiment to study the mechanisms by which Yap regulates muscle stem cell function.
Funding Notes:
Funding
Institute of Medical Sciences. Funding is available to UK or EU candidates only.
Eligibility
Candidates should have (or expect to achieve) a First Class or 2.1 Honours degree (or equivalent) in a relevant discipline.
References:
Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le DJ, Forcato M, Bicciato S, Elvassore N, & Piccolo S (2011). Role of YAP/TAZ in mechanotransduction. Nature 474, 179-183.
Sudol M & Harvey KF (2010). Modularity in the Hippo signaling pathway. Trends Biochem Sci 35, 627-633.
Watt KI, Judson R, Medlow P, Reid K, Kurth TB, Burniston JG, Ratkevicius A, De Bari C, & Wackerhage H (2010). Yap is a novel regulator of C2C12 myogenesis. Biochem Biophys Res Commun 393, 619-624.