Pitx2promotes development of splanchnic mesoderm-derived branchiomeric muscle

Abstract

Recent experiments, showing that both cranial paraxial and splanchnic mesoderm contribute to branchiomeric muscle and cardiac outflow tract (OFT) myocardium, revealed unexpected complexity in development of these muscle groups. The Pitx2 homeobox gene functions in both cranial paraxial mesoderm, to regulate eye muscle, and in splanchnic mesoderm to regulate OFT development. Here, we investigated Pitx2 in branchiomeric muscle. Pitx2 was expressed in branchial arch core mesoderm and both Pitx2 null and Pitx2 hypomorphic embryos had defective branchiomeric muscle. Lineage tracing with a Pitx2 cre allele indicated that Pitx2 mutant descendents moved into the first branchial arch. However, markers of both undifferentiated core mesoderm and specified branchiomeric muscle were absent. Moreover, lineage tracing with a Myf5 cre allele indicated that branchiomeric muscle specification and differentiation were defective in Pitx2 mutants. Conditional inactivation in mice and manipulation of Pitx2 expression in chick mandible cultures revealed an autonomous function in expansion and survival of branchial arch mesoderm.

Dynamic control of head mesoderm patterning

“…The head mesoderm markers Pitx2, Alx4, MyoR and Tbx1 pattern the head mesoderm prior to the formation of morphological boundaries and the onset of differentiation (Bothe and Dietrich, 2006), and mutations cause specific defects in craniofacial muscles and the outflow tract of the heart Dong et al, 2006;Gage et al, 1999;Harel et al, 2009;Kelly et al, 2004;Kitamura et al, 1999;Liu et al, 2002;Lu et al, 2002;Nowotschin et al, 2006;Sambasivan et al, 2009;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). …”

“…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.…”

Clonal analysis reveals common lineage relationships between head muscles and second heart field derivatives in the mouse embryo

“…This enhancer marks progenitors of the outflow tract and right ventricular myocardium (Verzi et al, 2005), as well as some branchial-arch-derived muscles (Dong et al, 2006).…”

“…Furthermore, the hierarchy of myogenic determination factors of the MyoD family differs between extraocular and branchiomeric muscles (Sambasivan et al, 2009). However, Pitx2 function is required for both extraocular and first-branchial-arch-derived muscles (Dong et al, 2006).…”

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 …”