Muscle development: Forming the head and trunk muscles (original) (raw)
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Proceedings of The National Academy of Sciences, 2007
Pitx2 expression is observed during all states of the myogenic progression in embryonic muscle anlagen and persists in adult muscle. Pitx2 mutant mice form all but a few muscle anlagen. Loss or degeneration in muscle anlagen could generally be attributed to the loss of a muscle attachment site induced by some other aspect of the Pitx2 phenotype. Muscles derived from the first branchial arch were absent, whereas muscles derived from the second branchial arch were merely distorted in Pitx2 mutants at midgestation. Pitx2 was expressed well before, and was required for, initiation of the myogenic progression in the first, but not second, branchial arch mesoderm. Pitx2 was also required for expression of premyoblast specification markers Tbx1, Tcf21, and Msc in the first, but not second, branchial arch. First, but not second, arch mesoderm of Pitx2 mutants failed to enlarge after embryonic day 9.5, well before the onset of the myogenic progression. Thus, Pitx2 contributes to specification of first, but not second, arch mesoderm. The jaw of Pitx2 mutants was vestigial by midgestation, but significant size reductions were observed as early as embryonic day 10.5. The diminutive first branchial arch of mutants could not be explained by loss of mesoderm alone, suggesting that Pitx2 contributes to the earliest specification of jaw itself.
PLoS ONE, 2013
Many differences exist between extraocular muscles (EOM) and non-cranial skeletal muscles. One striking difference is the sparing of EOM in various muscular dystrophies compared to non-cranial skeletal muscles. EOM undergo continuous myonuclear remodeling in normal, uninjured adults, and distinct transcription factors are required for the early determination, development, and maintenance of EOM compared to limb skeletal muscle. Pitx2, a bicoid-like homeobox transcription factor, is required for the development of EOM and the maintenance of characteristic properties of the adult EOM phenotype, but is not required for the development of limb muscle. We hypothesize that these unique properties of EOM contribute to the constitutive differences between EOM and non-craniofacial skeletal muscles. Using flow cytometry, CD34 + /Sca1 2/ CD45 2/ CD31 2 cells (EECD34 cells) were isolated from extraocular and limb skeletal muscle and in vitro, EOM EECD34 cells proliferated faster than limb muscle EECD34 cells. To further define these myogenic precursor cells from EOM and limb skeletal muscle, they were analyzed for their expression of Pitx2. Western blotting and immunohistochemical data demonstrated that EOM express higher levels of Pitx2 than limb muscle, and 80% of the EECD34 cells expressed Pitx2. siRNA knockdown of Pitx2 expression in EECD34 cells in vitro decreased proliferation rates and impaired the ability of EECD34 cells to fuse into multinucleated myotubes. High levels of Pitx2 were retained in dystrophic and aging mouse EOM and the EOM EECD34 cells compared to limb muscle. The differential expression of Pitx2 between EOM and limb skeletal muscle along with the functional changes in response to lower levels of Pitx2 expression in the myogenic precursor cells suggest a role for Pitx2 in the maintenance of constitutive differences between EOM and limb skeletal muscle that may contribute to the sparing of EOM in muscular dystrophies.
Cxcr4 and Sdf-1 are critically involved in the formation of facial and non-somitic neck muscles
Scientific Reports, 2020
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 (MyoG), which mediates terminal differentiation 12,13. In the Pax3/Pax7 double mutant mice, skeletal muscles of the trunk are severely compromised 11. Remarkably, myogenesis in the head does not rely on Pax3/Pax7 in this way 14. Pax3 is not involved in myogenesis in the head. During head muscle formation, expression of Pax7 follows the expression of Myf5 and MyoD, suggesting that Pax7 is not required to trigger skeletal myogenesis in the head 13. The Tbx1, Pitx2, Musculin (Msc) and Capsulin are thought to be linked to the control of myogenesis in this location 6,8,15 .
Pitx2 defines alternate pathways acting through MyoD during limb and somitic myogenesis
Development, 2010
The MyoD gene is part of the core regulatory network that governs skeletal myogenesis and acts as an essential determinant of the myogenic cell fate. Although generic regulatory networks converging on this gene have been described, the specific mechanisms leading to MyoD expression in muscles of different ontology remain misunderstood. We now show that the homeobox gene Pitx2 is required for initial activation of the MyoD gene in limb muscle precursors through direct binding of Pitx2 to the MyoD core enhancer. Whereas Myf5 and Mrf4 are dispensable for limb muscle progenitor fate, inactivation of Myf5 and Mrf4 in Pitx2 mutants results in a drastic decrease of limb MyoD expression. Thus, Pitx2 and Myf5 define parallel genetic pathways for limb myogenesis. We show a similar dependence on Pitx2 and Myf5(Mrf4) in myotome, where MyoD expression is initially activated by Myf5 and Mrf4. In their absence, MyoD expression is eventually rescued by a Pax3-dependent mechanism. We now provide evidence that Pitx2 contributes to the rescue of MyoD expression and that it acts downstream of Pax3. We thus propose that myogenic differentiation of somite-derived muscle cells relies on two parallel genetic pathways, with the Pitx2 pathway being of primary importance for limb myogenesis but the Myf5 and Mrf4 pathway predominating in myotome. Musclespecific wiring of regulatory networks composed of similar transcription factors thus underlies development of distinct skeletal muscles.
Frontiers in Cell and Developmental Biology
The knowledge of the molecular mechanisms that regulate embryonic myogenesis from early myogenic progenitors to myoblasts, as well as the emergence of adult satellite stem cells (SCs) during development, are key concepts to understanding the genesis and regenerative abilities of the skeletal muscle. Several previous pieces of evidence have revealed that the transcription factor Pitx2 might be a player within the molecular pathways controlling somite-derived muscle progenitors’ fate and SC behavior. However, the role exerted by Pitx2 in the progression from myogenic progenitors to myoblasts including SC precursors remains unsolved. Here, we show that Pitx2 inactivation in uncommitted early myogenic precursors diminished cell proliferation and migration leading to muscle hypotrophy and a low number of SCs with decreased myogenic differentiation potential. However, the loss of Pitx2 in committed myogenic precursors gave rise to normal muscles with standard amounts of SCs exhibiting hig...
Expression pattern of the homeodomain transcription factor Pitx2 during muscle development
Gene Expression Patterns, 2007
Late-stage Pitx2 +/LacZ mouse embryos stained with x-gal appeared to have blue muscles, suggesting that Pitx2 expression speciWcally marks some phase of the myogenic progression or muscle anlagen formation. Detailed temporal and spatial analyses were undertaken to determine the extent and onset of Pitx2 expression in muscle. Pitx2 was speciWcally expressed in the vast majority of muscles of the head and trunk in late embryos and adults. Early Pitx2 expression in the cephalic mesoderm, Wrst branchial arch and somatopleure preceded speciWcation of head muscle. In contrast, Pitx2 expression appeared to follow muscle speciWcation events in the trunk. However, Pitx2 expression was rapidly upregulated in these myogenic structures by E10.5. Upregulation correlated tightly with the apposition of a nonmyogenic, Pitx2-expressing, cell cluster lateral to the dermomyotome. This cluster Wrst appeared at the forelimb level at E10.25, gradually elongated in the posterior direction, appeared to aggregate from delaminated cells emanating from the ventrally located somatopleure, and was named the dorsal somatopleure. Immunohistochemistry on appendicular sections after E10.5 demonstrated that Pitx2 neatly marked the areas of muscle anlagen, that Pax3, Lbx1, and the muscle regulatory factors (MRFs) stained only subsets of Pitx2 + cells within these areas, and that virtually all Pitx2 + cells in these areas express at least one of these known myogenic markers. Taken together, the results demonstrate that, within muscle anlagen, Pitx2 marks the muscle lineage more completely that any of the known markers, and are consistent with a role for Pitx2 in muscle anlagen formation or maintenance.
The Emergence of Embryonic Myosin Heavy Chain during Branchiomeric Muscle Development
Life
A prerequisite for discovering the properties and therapeutic potential of branchiomeric muscles is an understanding of their fate determination, pattering and differentiation. Although the expression of differentiation markers such as myosin heavy chain (MyHC) during trunk myogenesis has been more intensively studied, little is known about its expression in the developing branchiomeric muscle anlagen. To shed light on this, we traced the onset of MyHC expression in the facial and neck muscle anlagen by using the whole-mount in situ hybridization between embryonic days E9.5 and E15.5 in the mouse. Unlike trunk muscle, the facial and neck muscle anlagen express MyHC at late stages. Within the branchiomeric muscles, our results showed variation in the emergence of MyHC expression. MyHC was first detected in the first arch-derived muscle anlagen, while its expression in the second arch-derived muscle and non-somitic neck muscle began at a later time point. Additionally, we show that no...