Cxcr4 and Sdf-1 are critically involved in the formation of facial and non-somitic neck muscles

Abstract

The present study shows that the CXCR4/SDF-1 axis regulates the migration of second branchial archderived muscles as well as non-somitic neck muscles. Cxcr4 is expressed by skeletal muscle progenitor cells in the second branchial arch (BA2). Muscles derived from the second branchial arch, but not from the first, fail to form in Cxcr4 mutants at embryonic days E13.5 and E14.5. Cxcr4 is also required for the development of non-somitic neck muscles. in Cxcr4 mutants, non-somitic neck muscle development is severely perturbed. In vivo experiments in chicken by means of loss-of-function approach based on the application of beads loaded with the CXCR4 inhibitor AMD3100 into the cranial paraxial mesoderm resulted in decreased expression of Tbx1 in the BA2. Furthermore, disrupting this chemokine signal at a later stage by implanting these beads into the BA2 caused a reduction in MyoR, Myf5 and MyoD expression. In contrast, gain-of-function experiments based on the implantation of SDF-1 beads into BA2 resulted in an attraction of myogenic progenitor cells, which was reflected in an expansion of the expression domain of these myogenic markers towards the SDF-1 source. Thus, Cxcr4 is required for the formation of the BA2 derived muscles and non-somitic neck muscles.In vertebrates, trunk muscles originate from the somites, whereas most of the head muscles originate from the cranial paraxial mesoderm (CPM) 1,2 . Neck muscle progenitor cells are found in the transition zone between somite and CPM 3,4 . The CPM cells transiently migrate laterally into the region of the branchial arches and contributes to the muscles of the head 5,6 . These muscles can be divided into branchial, extra-ocular (EOM), axial and laryngoglossal muscles 2 . BAs are made of surface ectoderm, endoderm, myogenic mesodermal cells and neural crest cells (NCCs) 7 . The BA1 mesoderm contributes to formation of mastication muscles. The BA2 mesoderm gives rise to facial expression muscles 8 . Skeletal muscle progenitor cells in the more caudal BAs (3rd, 4th and 6th) are thought to contribute to neck muscles, for example the trapezius and sternocleidomastoideus, or its birds homologue the cucullaris muscle 3,4 . Clonal analysis reports that trapezius and sternocleidomastoid neck muscles are formed from non-somitic progenitor cells, whereas splenius muscle and laryngeal muscles have a dual origin (somitic and non-somitic) of the progenitor cells 3,4 . The genetic regulation of craniofacial myogenesis remains to be fully elucidated 5,8-10 .The signaling cascades that control pre-myogenic progenitor cell specification act distinctly in the head and trunk muscles 1,8 . Several pre-myogenic genes that are required to initiate myogenesis and maintain cells in an immature state in the trunk are known. Pax3, Pax7 and Lbx1 are crucial in specifying pre-myogenic progenitor cells in the dermomyotomes, the parts of the somites that gives rise to trunk and limb myoblasts 8,11 . The expression of Pax3 and Pax7 in somites is normally downregulated before activation of Myogenin...

The CXCR4/SDF-1 Axis in the Development of Facial Expression and Non-somitic Neck Muscles

“…which was reflected in an enlargement of the expression domain of myogenic regulatory factors around SDF-1 beads (Figure 6bC; Yahya et al, 2020b). In contrast, control PBS beads didnt't show any change in the expression (Figures 6aC,6bB).…”

“…More recently, we revealed that the chemokine receptor CXCR4 and its ligand SDF-1 have a critical role in the facial muscles development in the chicken and mouse embryos. At E10.5, we found that CXCR4 is expressed in the migrating muscle progenitor cells in the core of the BA2 and SDF-1 is detected in the BA2 endoderm in proximity to these progenitor cells ( Yahya et al, 2020b ). Later, CXCR4 is already transcribed in all BA2-derived muscle progenitor cells, but not BA1-derived muscle progenitor cells ( Figure 5A ).…”

“…In contrast to our understanding of the role of CXCR4/SDF-1 axis in the trunk muscles development, less is known about its role in formation of the head and neck muscles. We have recently provided evidence that disruption of CXCR4/SDF-1 signaling also impairs facial and non-somitic neck muscles formation ( Yahya et al, 2020b ). This review summarizes the main roles of the CXCR4/SDF-1 axis in skeletal muscle development, concerning the special emphasis on the development of the BA2 and non-somitic neck muscles.…”

“…CXCR4 is also noticed in non-somitic neck muscles (sternocleidomastoideus, s-trapezius and a-trapezius) ( Figure 5A ). SDF-1 showed a complementary expression pattern in the regions that correspond to the BA2-derived muscle anlagen ( Figure 5B ) ( Yahya et al, 2020b ). Thus, these CXCR4 and SDF-1 expression patterns correlate closely with the migration of second arch-derived muscle progenitor cells, as well as the non-somtic neck muscle cells.…”

“…Furthermore, SDF-1 positively regulates the expression of irregular connective tissue markers during limb development and controls the formation of blood vessels in the somite ( Abduelmula et al, 2016 ; Nassari et al, 2017 ). Recently, we reported that CXCR4/SDF-1 axis has a crucial role in facial and neck muscle development ( Yahya et al, 2020b ).…”