Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch

Abstract

Pitx2 expression is observed during all states of the myogenic progression in embryonic muscle anlagen and persists in adult muscle. Pitx2 mutant mice form all but a few muscle anlagen. Loss or degeneration in muscle anlagen could generally be attributed to the loss of a muscle attachment site induced by some other aspect of the Pitx2 phenotype. Muscles derived from the first branchial arch were absent, whereas muscles derived from the second branchial arch were merely distorted in Pitx2 mutants at midgestation. Pitx2 was expressed well before, and was required for, initiation of the myogenic progression in the first, but not second, branchial arch mesoderm. Pitx2 was also required for expression of premyoblast specification markers Tbx1, Tcf21, and Msc in the first, but not second, branchial arch. First, but not second, arch mesoderm of Pitx2 mutants failed to enlarge after embryonic day 9.5, well before the onset of the myogenic progression. Thus, Pitx2 contributes to specification of first, but not second, arch mesoderm. The jaw of Pitx2 mutants was vestigial by midgestation, but significant size reductions were observed as early as embryonic day 10.5. The diminutive first branchial arch of mutants could not be explained by loss of mesoderm alone, suggesting that Pitx2 contributes to the earliest specification of jaw itself.homeobox gene ͉ muscle development

Velo‐cardio‐facial syndrome: 30 Years of study

“…It is also probable that there is downstream and upstream interaction between genes in the deleted region and genes elsewhere in the genome. Several of these interactions and regulatory functions have already been reported, including the interactions of TBX1, a gene always deleted in VCFS, with VEGF, PITX, and FGF10 [Stalmans et al, 2003;Kelly et al, 2004;Shih et al, 2007]. The role of gene dosage within the 22q11.2 region has been the subject of many studies within the past decade because of the hope that one or more of the deleted genes will be found to contribute to psychiatric illness and/or cognitive impairment.…”

“…It is also possible that TBX1 is involved in a more complex mechanism of heart development that involves downstream regulation of other genes or complex genetic interactions of multiple genes. There is good evidence that TBX1 interacts several genes important to embryogenesis including several homeobox genes that are highly involved in the regional development of the pharyngeal arches and pouches that form the structures of the head and neck and portions of the heart and its vascular system (Merscher et al, 2001;Kelly et al, 2004;Stalmans et al, 2003;Shih et al, 2007).…”

Dynamic control of head mesoderm patterning

“…Pitx2, MyoR and Tbx1 have been shown to keep cells in an undifferentiated, proliferative precursor state, but contribute to the onset of myogenesis in a similar fashion as Pax3 in the somite (Kioussi et al, 2002;Lu et al, 1999;Martinez-Fernandez et al, 2006;Sambasivan et al, 2009;Xu et al, 2004). Mutations of the genes cause specific defects in the head musculature and outflow tract of the heart Dong et al, 2006;Gage et al, 1999;Kelly et al, 2004;Kitamura et al, 1999;Liu et al, 2002;Lu et al, 2002;Nowotschin et al, 2006;Shih et al, 2007;Vitelli et al, 2002a;Vitelli et al, 2002b;Xu et al, 2004) (for reviews, see Baldini, 2002;Bothe et al, 2007;Noden and Francis-West, 2006;Rochais et al, 2009). Thus, the head mesoderm genes are crucial upstream regulators, and their correct deployment is an essential step in head muscle and heart formation.…”

Many routes to the same destination: lessons from skeletal muscle development

“…Interestingly, these non-somite-derived muscles also have some distinct molecular mechanisms driving their differentiation and do not express PAX3/7 but instead are specified by other transcription factors such as PITX2 (Dong et al 2006, Shih et al 2007) and TBX1 (Dastjerdi et al 2007); mice carrying mutations in these genes show defects in head muscle development, while overexpression studies in cultured chicken embryo …”