Gene regulatory networks and cell lineages that underlie the formation of skeletal muscle

Abstract

Skeletal muscle in vertebrates is formed by two major routes, as illustrated by the mouse embryo. Somites give rise to myogenic progenitors that form all of the muscles of the trunk and limbs. The behavior of these cells and their entry into the myogenic program is controlled by gene regulatory networks, where paired box gene 3 (Pax3) plays a predominant role. Head and some neck muscles do not derive from somites, but mainly form from mesoderm in the pharyngeal region. Entry into the myogenic program also depends on the myogenic determination factor (MyoD) family of genes, but Pax3 is not expressed in these myogenic progenitors, where different gene regulatory networks function, with T-box factor 1 (Tbx1) and paired-like homeodomain factor 2 (Pitx2) as key upstream genes. The regulatory genes that underlie the formation of these muscles are also important players in cardiogenesis, expressed in the second heart field, which is a major source of myocardium and of the pharyngeal arch mesoderm that gives rise to skeletal muscles. The demonstration that both types of striated muscle derive from common progenitors comes from clonal analyses that have established a lineage tree for parts of the myocardium and different head and neck muscles. Evolutionary conservation of the two routes to skeletal muscle in vertebrates extends to chordates, to trunk muscles in the cephlochordate Amphioxus and to muscles derived from cardiopharyngeal mesoderm in the urochordate Ciona, where a related gene regulatory network determines cardiac or skeletal muscle cell fates. In conclusion, Eric Davidson's visionary contribution to our understanding of gene regulatory networks and their evolution is acknowledged.

Keywords: cell lineages; gene regulatory networks; muscle origins; second heart field; skeletal myogenesis.

Fig. 1.

Gene regulatory networks at the onset of myogenesis in the trunk and limbs, where Pax3 plays a central role in controlling many aspects of myogenic progenitor cell behavior (A) including choice of the myogenic cell fate, survival, proliferation, migration, and entry into the differentiation program, which depends on activation of the myogenic determination genes at different sites where skeletal muscle formation is initiated in the mouse embryo (B). derm refers to the dorsal dermis.

Fig. 2.

Gene regulatory networks that control the formation of head muscles, highlighting the role of Tbx1 and Pitx2 in extraocular and first branchial arch-derived myogenic progenitors, for which most functional information is available in the mouse embryo.

Fig. 3.

A lineage tree for the myocardium of the heart and for nonsomitic head and neck muscles (in bold), based on retrospective clonal analyses in the mouse embryo. In the case of nonsomitic neck muscles, clonal analysis focused on the trapezius and sternocleidomastoid muscles. The two myocardial lineages can be compared with the two heart fields that constitute sources of equivalent parts of the myocardium. a, anterior; FHF, first heart field; p, posterior.