Résumé :
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Pitx2 and Pitx3 genes are members of the Pitx gene family that encodes homeodomain transcription factors. Originally identified as important upstream regulators in the pituitary gland, Pitxs play a role in the formation of a number of tissues and organs where they have been implicated in regulating programs of tissue differentiation, and progenitor cell proliferation and survival. During muscle development, Pitx2 is expressed in progenitor cells and early differentiating cells, while Pitx3 expression starts in progenitors and is maintained in differentiated cells. We previously showed that Pitx2 is directly required for MyoD gene induction in embryonic limb bud precursors through its direct binding to the MyoD -20 kb enhancer, and also contributes, downstream of Pax3, to MyoD gene expression in the myotome. Pitx3-/- mice are viable and fertile and do not show obvious phenotype during muscle development: in wild-type muscles Pitx2 expression mainly occurs in muscle progenitors and decreases during differentiation. However, in Pitx3-/- muscles this expression is maintained in differentiated cells, suggesting functional overlapping between both genes. Using conditional targeted deletion in mice, we show that inactivation of both Pitx2/3 genes in muscle progenitors leads to major muscle hypoplasia during development, due to extensive apoptosis. Surprisingly, this apoptosis is not observed in muscle progenitors marked by expression of Pax3 and Pax7, but rather in differentiating myoblasts. Such apoptosis is not observed when inactivation of Pitx2/3 genes is targeted to differentiated myotubes (Pitx2F/F; Pitx3F/F;HSA-Cre) suggesting an essential role of Pitx genes in the survival of myoblasts during cell cycle exit and initial steps of differentiation. Similarly to what we have observed during embryonic development, Pitx2 is present in adult quiescent satellite cells and during their activation, but is down-regulated upon differentiation, while Pitx3 expression is induced during activation and maintained in differentiated myotubes. In addition, Pitx3-/- satellite cells display maintenance of Pitx2 expression during differentiation. The role of Pitx2 and Pitx3 in postnatal muscle growth and regeneration is currently under investigation using conditional targeted deletion in satellite cells.
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