During embryonic development the integration of numerous synergistic signalling pathways turns a single cell into a multicellular organism with specialized cell types and highly structured, organized tissues. To achieve this, cells must grow, proliferate, differentiate and die according to their spatiotemporal position. Unravelling the mechanisms by which a cell adopts the correct fate in response to its local environment remains one of the fundamental goals of biological research. In vertebrates skeletal myogenesis is orchestrated by the activation of the myogenic regulatory factors (MRFs) in response to signals that are interpreted by their associated regulatory elements in different precursor cells during development. The MRFs trigger a cascade of transcription factors and downstream structural genes, ultimately resulting in the generation of one of the fundamental histotypes.
Myf5, the first of these MRFs to be activated in the mouse embryo, is first expressed in the dorsomedial lip of the dermomyotome. In the absence of Myf5, the myogenic process is delayed for 48h. The phenotype is rescued by the activation of another member of the MRF family, MyoD. In the double Myf5/MyoD KO animals there is no rescue of the phenotype and they lack all skeletal musculature.
To further investigate the function of Myf5, we have generated a new inducible KO strain in which the enhancer element that drives the first wave of Myf5 expression in the dermomyotomal lip can be deleted from the genome. Preliminary data show that this domain of expression has been specifically targeted.
We plan to fully characterise the new KO strain and to study the effects of eliminating Myf5 function only from the dorsomedial lip. Furthermore, we will cross it with the MyoD KO strain in order to block myogenesis only this precursor cell population. This should result in a better understanding of the function of Myf5 and of the contribution of dorsomedial lip derivatives to adult skeletal musculature.
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