Endothelial cell specification in the somite is compromised in Pax3-positive progenitors of Foxc1/2 conditional mutants, with loss of forelimb myogenesis

Abstract

Pax3 and Foxc2 have been shown genetically to mutually repress each other in the mouse somite. Perturbation of this balance in multipotent cells of the dermomyotome influences cell fate; upregulation of Foxc2 favours a vascular fate, whereas higher levels of Pax3 lead to myogenesis. Foxc1 has overlapping functions with Foxc2. In Foxc1/2 double-mutant embryos, somitogenesis is severely affected, precluding analysis of somite derivatives. We have adopted a conditional approach whereby mutations in Foxc1 and Foxc2 genes were targeted to Pax3-expressing cells. Inclusion of a conditional reporter allele in the crosses made it possible to follow cells that had expressed Pax3. At the forelimb level, endothelial and myogenic cells migrate from adjacent somites into the limb bud. This population of endothelial cells is compromised in the double mutant, whereas excessive production of myogenic cells is observed in the trunk. However, strikingly, myogenic progenitors fail to enter the limbs, leading to the absence of skeletal muscle. Pax3-positive migratory myogenic progenitors, marked by expression of Lbx1, are specified in the somite at forelimb level, but endothelial progenitors are absent. The myogenic progenitors do not die, but differentiate prematurely adjacent to the somite. We conclude that the small proportion of somite-derived endothelial cells in the limb is required for the migration of myogenic limb progenitors.

A critical role for the nuclear protein Akirin2 in the formation of mammalian muscle in vivo

“…At E10.5, there was a complete absence of Pax3‐positive muscle precursors in the forelimbs of Aki2 SimKO mutants; while there was extensive overlap of Pax3 and tdTom in the forelimb bud in controls, the reduced number of tdTom‐positive cells in the mutant forelimb bud did not co‐express Pax3 (Figure a). The population of remaining tdTom‐positive cells in the mutant appeared to be largely made up of somite‐derived endothelial cells that are PECAM1/CD31‐positive (Mayeuf‐Louchart et al, ) (Figure b). At later developmental time points, there was a similar absence of Pax7‐positive myogenic progenitors in the Aki2 SimKO mutant forelimb (Figure c, E11.5; Figure d, E14.5).…”

Dermomyotome-derived endothelial cells migrate to the dorsal aorta to support hematopoietic stem cell emergence

“…Because somitic Etv2 + cells are localized specifically within the dermomyotome region, the muscle progenitor cell compartment of the somite, a conserved mechanism of SDEC generation may be shared among vertebrates (Pouget et al, 2006 ;Mayeuf-Louchart et al, 2014;Mayeuf-Louchart et al, 2016).…”

Axial and limb muscle development: dialogue with the neighbourhood

“…3c) [9,23]. The influence of this tissue is part of the MPC emigration system, although the signals involved have not yet been identified.…”

“…In fact, it is becoming increasingly evident that tissues surrounding myogenic cells are not only crucial during early myogenesis but also later in development as muscle masses interact with other tissues of the musculoskeletal system (e.g. [8][9][10]). Defects in these interactions can lead to diseases such as congenital diaphragmatic hernias [8] or congenital myasthenia [11].…”