Although head muscles resemble limb and trunk muscles in myofiber architecture, their developmental history is widely divergent [11]. Branchiomeric muscles and their accompanying muscle stem cells develop from the cranial mesoderm (also known as pharyngeal mesoderm), which includes both the cranial paraxial mesoderm and lateral splanchnic mesoderm [1,25,26,27,28]. The pharyngeal mesoderm forms the mesodermal core within the pharyngeal arches (also known as branchial arches), which are transitory structures in the vertebrate embryo that bulge ventrally in pairs from the pharynx [1,5]. Each arch comprises a mesodermal core surrounded by neural crest cells, endoderm, and ectoderm, which tightly influence mesodermal cell development [26,29]. The mesodermal core of the pharyngeal arches gives rise to the branchiomeric muscles and significant parts of the heart [1,6,26,29,30,31,32,33,34]. The first and second pharyngeal arches give rise to masticatory and facial expression muscles, and posterior pharyngeal arches give rise to non-somitic neck muscles and esophagus striated muscles, respectively (Figure 1) [1,6,25,26,28,31,35]. Moreover, a recent mouse genetic lineage analysis revealed that pharyngeal mesoderm contributes to the medial pharyngeal skeleton and branchiomeric muscle elements (connective tissue) [36].

Overall, the early stages of the myogenic progression can be followed by switching on the basic helix–loop–helix myogenic regulatory factors MyoD, Myf5, myogenin (MyoG), and MRF4 in all areas of the body [8] (Figure 2). In the trunk, Pax3 and Pax7 are expressed in the somites as soon as they form [2,12]. Pax3 keeps myogenic precursor cells in a proliferative state, but contributes to the onset of myogenesis and thus is referred to as a premyogenic gene [2]. In the somitic mesoderm, MyoD and Myf5 are expressed first, committing cells to myogenesis, and are therefore known as myogenic determination factors [2,12]. While trunk muscle progenitor cells require Pax3 expression for activating myogenic progression, branchiomeric muscle progenitor cells are regulated by a Pax3-independent regulatory network [8,25]. Branchiomeric muscles express a remarkably heterogeneous set of genes in both the embryo and adult. Molecular and technical advances in the last 20 years have provided comprehensive information about the genetic regulation of these muscles. Their myoblasts are specified by Pitx2, Tbx1, Islet1, musculin, and Capsulin genes ([7,8,14,25,37]). These genes also distinguish branchiomeric muscle satellite cells from satellite cells in the trunk [37,38,39]. Tbx1, Pitx2, and MyoR have been shown to maintain myogenic progenitor cells in an undifferentiated state, but are also required to initiate myogenesis similarly to Pax3 in the trunk [7,37,40,41,42,43,44]. Although all branchiomeric muscles share a common embryonic origin, the upstream factors involved in each pharyngeal arch are varied. In the mouse, Pitx2 is expressed in the mesodermal core of the first pharyngeal arch at E9.5. It acts to assure the expression of pre-myogenic genes Tbx1, Capsulin, and Musculin in the first arch-derived muscle, but not the second arch muscle [8]. Importantly, the first, but not second, arch mesoderm of Pitx2-null embryos failed to activate these transcription factors after E 9.5. Thus, Pitx2 is required to initiate the myogenic progression in the first arch mesoderm, but not in other pharyngeal arches [8,14]. The onset of myogenic progression in the second and most caudal pharyngeal arches is regulated by Tbx1, which regulates Myf5 and MyoD (Figure 2) [14,43]. In the absence of Tbx1, the caudal pharyngeal arches do not form, resulting in the absence of muscles developed from most caudal arches, including those of the larynx and esophagus [6,25,35]. Although Tbx1 is not required for the migration of the pharyngeal mesoderm into the first pharyngeal arch [43], it is required for the correct patterning of muscles with pharyngeal-mesoderm-derived connective tissue [36]. Previously, we reported on a fate-mapping experiment based on EGFP-based cell labeling and quail–chicken cell injection that found that chicken second pharyngeal arch progenitor cells contributed to the heart muscle in vivo [33]. We also reported that the chemokine receptor CXCR4 was required for the migration of pharyngeal mesoderm into the second and most caudal pharyngeal arches, but not the first pharyngeal arch. Interestingly, we also reported a reduction in muscles derived from the caudal pharyngeal arches (non-somitic neck muscle) in CXCR4 mutants [27,28]. Taken together, these findings suggested that the genetic programs promoting branchiomeric myogenesis in the various pharyngeal arches are widely divergent.