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Core issues in craniofacial myogenesis
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Review
Core issues in craniofacial myogenesis Robert G. Kelly⁎ Developmental Biology Institute of Marseilles-Luminy, UMR6216 CNRS Université de la Méditerranée, Campus de Luminy Case 907, 13288 Marseille Cedex 9 France
A R T I C L E I N F O R M A T I O N
A B S T R A C T
Article Chronology:
Branchiomeric craniofacial muscles control feeding, breathing and facial expression. These
Received 1 March 2010
muscles differ on multiple counts from all other skeletal muscles and originate in a progenitor cell
Revised version received 23 April 2010
population in pharyngeal mesoderm characterized by a common genetic program with an
Accepted 28 April 2010
adjacent population of cardiac progenitor cells, the second heart field, that gives rise to much of the
Available online 8 May 2010
heart. The transcription factors and signaling molecules that trigger the myogenic program at sites of branchiomeric muscle formation are correspondingly distinct from those in somite-derived
Keywords:
muscle progenitor cells. Here new insights into the regulatory hierarchies controlling
Skeletal muscle
branchiomeric myogenesis are discussed. Differences in embryological origin are reflected in
Craniofacial development
the lineage, transcriptional program and proliferative and differentiation properties of
Tbx1
branchiomeric muscle satellite cells. These recent findings have important implications for our
Heart development
understanding of the diverse myogenic strategies operative both in the embryo and adult and are of direct biomedical relevance to deciphering the mechanisms underlying the cause and progression of muscle restricted myopathies. © 2010 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulatory networks controlling branchiomeric myogenesis . . . . . . Reinforcing links between heart and head muscle development . . . . New insights into the origins and properties of branchiomeric satellite Evolutionary considerations . . . . . . . . . . . . . . . . . . . . . . . Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Branchiomeric craniofacial skeletal muscles are involved in feeding, breathing and facial expression, rather than locomotion, and
⁎ Fax: +33 491269726. E-mail address: [email protected]. 0014-4827/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yexcr.2010.04.029
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originate from cranial mesoderm in the core of the bilateral branchial (or pharyngeal) arches. The progenitor cell populations that give rise to these muscles have recently been shown to share the genetic signature of an adjacent population of pharyngeal mesodermal cells
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that contribute to myocardium at the poles of the heart tube during cardiac looping, a progenitor cell population termed the second heart field [1,2]. This observation highlights the visceral nature of branchiomeric skeletal muscles which thus differ fundamentally from all other skeletal muscles in the embryo that are derived from somites (trunk, limb, ventral pharyngeal and tongue muscles) or prechordal mesoderm (extraocular muscles). Furthermore, the two myogenic fates of pharyngeal mesoderm provide additional evidence for a cardiocraniofacial field underlying normal and pathological head and heart development [3]. Here recent embryological and molecular insights into the regulation of branchiomeric myogenesis, together with new findings as to the origins and properties of branchiomeric muscle satellite cells will be reviewed. These data consolidate and expand our understanding of the mechanisms regulating common and divergent features of head and heart muscle development and provide a framework for deciphering mechanisms underlying the origin and progression of muscle restricted myopathies. A number of recent reviews have detailed the multiple points distinguishing branchiomeric craniofacial muscles from other skeletal muscles in the embryo [1,2,4]. These include embryonic origin, in cranial mesoderm rather then somites; function, in feeding, breathing and facial expression rather than locomotion; motor innervation, branchiomeric motor neurons having visceral rather than somatic motor columns; the cis and trans regulation of the genes encoding the myogenic determination factors Myf5 and MyoD. In the last year several papers have shown that despite an apparent convergence of branchiomeric skeletal muscles with the skeletal muscle program of all other muscles after activation of these myogenic determination genes, certain distinguishing features remain. In particular, these concern branchiomeric skeletal muscle stem cells or satellite cells, that reflect their origin in pharyngeal cranial mesoderm and the common history with their developmental neighbors, cardiac progenitor cells of the second heart field [5–7]. Before discussing these new papers, we will consider the embryology and molecular regulation of branchiomeric muscles. Initiation of the myogenic program occurs in the mesodermal core of each of the five bilateral branchial arches, each comprised of pharyngeal epithelia, ectoderm and endoderm, surrounding a neural crestderived mesenchymal cell population and a central relatively compact mesodermal core (Fig. 1A; [8]). Importantly for this review, each arch also contains an artery connecting the arterial pole of the heart to the descending aorta. The first branchial arch will form the mandible of jawed vertebrates; whereas in fish the posterior branchial arches are maintained as gills, in amniotes they are transient structures that during subsequent development give rise to components of the face and neck. The arch arteries are remodeled to generate arteries of the head and the great vessels connecting the definitive ventricular outlets to the descending aorta and pulmonary arteries [8].
Regulatory networks controlling branchiomeric myogenesis The colonization of the arches by core mesoderm is thought to occur by lateral movement of preotic cranial mesoderm with a splanchnic mesodermal contribution in the distal region of the arch [4,9–11]. However, unlike mesoderm at the level of the somites, cranial mesoderm is not morphologically divided into paraxial, intermedi-
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ate and lateral domains and proximodistal patterning of core arch mesoderm appears to reflect a dynamic continuum along the medial–lateral embryonic axis (Fig. 1A). Myf5 and MyoD are known to be the two key regulatory factors driving determination of branchiomeric myogenesis within core arch mesoderm and in their absence craniofacial myogenesis fails, whereas trunk muscle development is rescued by Mrf4 [12,13]. The enhancers driving Myf5 activation in the arches are dispersed over a large upstream region of the gene and include elements operating in specific arches, an illustration of the fact that branchiomeric myogenesis in turn represents a composite of subprograms and myogenic strategies operating in different regions of the arches and in different arches themselves [14]. The transcription factors known to operate upstream of Myf5 and MyoD in branchiomeric muscle development also differ from those identified in developing somites. The paired homeoprotein Pax3 is expressed in developing somites but not sites of branchiomeric muscle development; trunk and limb myogenesis, but not head muscle development, fails in Pax3 Myf5 double mutant embryos, Pax3 being required for Myf5-independent MyoD activation in somite-derived muscles [15]. In contrast, four transcription factors have been identified that play specific roles in branchiomeric myogenesis. Capsulin (Tcf21) and MyoR, two bHLH transcriptional repressors, are together required for Myf5 activation in the mandibular arch and in double mutant embryos cell death is elevated in core mesoderm resulting in a failure to develop jaw closing muscles derived from the proximal first arch [16]. Pitx2, a homeobox transcription factor, is required for extraocular muscle development in prechordal mesoderm and differentiation and survival of myogenic progenitors in the first arch [17,18]. The Tbox containing transcriptional activator Tbx1 regulates robust bilateral activation of Myf5 and MyoD in all branchiomeric muscles, defining a subset of craniofacial muscles as Tbx1-dependent branchiomeric muscles, including laryngeal muscles and the cervical component of the trapezius muscle (Fig. 1B; [19–21]). Differentiation of extraocular muscles and tongue musculature is Tbx1 independent, although intriguingly developing tongue muscles express Tbx1 [22]. Stochastic activation of myogenesis in the absence of Tbx1 results in the formation of hypoplastic, frequently unilateral skeletal muscles that appear to have normal patterning and to be colonized by Pax7 positive cells with normal proliferative and differentiation capacities (Fig. 2A; [21]). Tbx1 is thus not absolutely required for the activation of branchiomeric myogenesis but rather ensures that the specification step occurs robustly; once this early requirement for Tbx1 is bypassed normal myogenesis ensues [19,21]. Arches 2–6 are extremely hypoplastic in Tbx1 null embryos, reflecting the fact that this gene plays additional upstream roles in pharyngeal morphogenesis. The molecular mechanisms by which these four transcription factors regulate branchiomeric myogenesis, including identification of direct targets and potential interactions, remain unknown. The mesodermal core of the branchial arches is exposed to a variety of intercellular signals, emanating from pharyngeal epithelia, neural crest cells and autocrine sources. Intercellular signaling pathways differ in their impact on the myogenic program in the head and trunk [1,2,4]. Interest has focused on Wnt, bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signaling in regulating early events of branchiomeric myogenesis. Wnt signaling appears to be important in maintaining the progenitor cell state in pharyngeal mesoderm and delaying myogenic differentiation [11,23,24]. Intriguingly, delayed differentiation after activation of
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Fig. 1 – Branchiomeric craniofacial myogenesis. (A) Left: cartoon contrasting cranial and trunk mesoderm in the early embryo; middle: MyoD transcript distribution at midgestation in sites of somite-derived and branchiomeric myogenesis; right: schematic sections though the early head region and branchial arch region corresponding to the dashed lines i and ii. P and D indicate the proximodistal arch axis. (B) Left lateral, dorsal and submandibular views of embryos showing MyoD transcript distribution and Myf5-nlacZ transgene expression. Note the loss of branchiomeric craniofacial muscles in Tbx1 mutant embryos including mandibular muscles (m), muscles of facial expression (f), muscles of the larynx, pharynx (p) and the cervical trapezius (arrowhead) but not tongue muscles (t). The genetic dissection of a subset of craniofacial muscles observed in the absence of Tbx1 is comparable to sequential dissection of neck muscles in a human cadaver. Adapted with permission from references [1], [19] and [49].
myogenic determination genes is another distinction between branchiomeric and somite-derived myogenesis, potentially linked with the need to correctly position the primordia of jaw operating and facial expression muscles during morphogenesis of the head.
BMP signaling has been proposed to drive the cardiac differentiation program in distal arch mesoderm during heart tube elongation, while FGF signaling promotes cardiac progenitor cell proliferation [5,25,26]. A recent study in the zebrafish has found that FGF, but not
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Fig. 2 – The pharyngeal myogenic lineage. (A) Comparison of Tbx1 dependent and Isl1 lineage derived craniofacial muscles. Branchiomeric but not extraocular (eom) or tongue (t) muscles are Tbx1-dependent and derived from Isl1 expressing progenitor cells. Note the sporadic hypoplastic right masseter (asterisk), facial expression (arrowhead) and anterior digastric muscles in the Tbx1 mutant embryo labeled by a Myf5-nlacZ transgene. Almost all muscles of facial expression and the left masseter are absent; affected muscles correspond to those expressing β-galactosidase activated by Isl1-Cre. (B) Cartoon showing the contribution of pharyngeal mesoderm to branchiomeric skeletal muscles and second heart field derived components of the heart. The remainder of the heart is derived from lateral splanchnic mesoderm and other skeletal muscles are derived from somites (trunk, limb, ventral pharyngeal and tongue muscles) or prechordal cranial mesoderm (extraocular muscles). The properties of somitic and branchiomeric muscle satellite cells reflect the origin of their associated muscles. Adapted with permission from references [1] and [11]. Notch, Hedgehog or BMP signaling, is required for activation of engrailed2, encoding a homeodomain transcription factor, in the dorsal first arch, a readout likely reflecting patterning of core mesoderm in the first arch [27]. Expression of engrailed2 was also found to be dependent on the fish homologue of Tbx1, vgo, although Tbx1, as well as Capsulin expression, was unaltered in embryos cultured in the presence of FGF signaling pathway inhibitors. These experiments also found that FGF signaling is continuously required to maintain the branchiomeric myogenic program after specification [27]. The expression of certain FGF ligand and receptor encoding genes is known to be Tbx1dependent in the mouse, suggesting that FGF signaling may act downstream of Tbx1 function, although analysis of ace zebrafish mutants (lacking Fgf8) and Fgf10 null mouse embryos has shown that these ligands are not individually required for the activation of branchiomeric myogenesis [19,27]. Fgf8, however, appears to play a role in promoting branchiomeric over extraocular myogenesis, potentially polarizing the proximodistal axis of the arch [28]. The zebrafish study also ruled out a major role for signals from the neural tube or pharyngeal endoderm in the activation of engrailed2 expression, consistent with studies in chick embryos and suggesting that the
specification of branchiomeric muscles is a highly robust and potentially cell-autonomous process [27,28]. A detailed genetic analysis in the mouse has yielded important insight into the regulatory hierarchies in branchiomeric muscle development, as well as fundamental insights into the hierarchies regulating extraocular muscle development beyond the scope of this short review [6]. Analysis of embryos doubly mutant for Tbx1 and Myf5 revealed that the stochastic formation of hypoplastic muscles observed in Tbx1 null embryos was severely impaired, although not completely abolished, in the absence of both genes [6]. This reveals that Myf5 must be required for most of the residual myogenesis occurring in Tbx1 mutant embryos and furthermore that the activation of MyoD that normally rescues craniofacial myogenesis in Myf5 mutant embryos must be Tbx1 driven [6,12]. Thus Tbx1 sits upstream of MyoD in the branchiomeric myogenic hierarchy, in a similar position to Pax3 in trunk myogenesis. Given that Tbx1 also regulates Myf5, Tbx1 is likely to be situated in an outer layer of the regulatory circuit surrounding the core myogenic program in head myogenesis [6]. Analysis of craniofacial myogenesis in the zebrafish has revealed that the functions of Myf5 and MyoD are non-redundant during branchiomeric muscle development and has implicated the homeodomain transcription factor Six1 in the maintenance of the
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branchiomeric myogenic program [29,30]. Six1 is activated after Myf5 during branchiomeric myogenesis and appears to be independent of the Tbx1 pathway, also playing a Pax3-like role upstream of MyoD in branchiomeric muscle differentiation [30]. This study also provides genetic evidence that Tbx1 directly activates Myf5, since Myf5 cDNA, but not that of MyoD or Six1, rescued myogenesis after Tbx1 knockdown [30]. Six1, together with Six4, is required for formation of certain muscles in the mouse, although a specific role in branchiomeric myogenesis has not been observed [31].
Reinforcing links between heart and head muscle development The contribution of mesoderm associated with the gut to head musculature was noted by Romer who highlighted the visceral nature of branchiomeric skeletal muscles: “branchial and gut muscles, striated or smooth, are but the anterior and posterior parts of a single great visceral system of muscles whose primary locus is in the walls of the digestive tract” [32]. Molecular genetic analysis now largely corroborates this visceral view of branchiomeric myogenesis and supports the hypothesis of a common developmental and evolutionary origin with another myogenic derivative of visceral mesoderm, myocardium. Indeed, recent data has demonstrated that pharyngeal mesoderm gives rise not only to branchiomeric skeletal muscles but also to part of the heart. Among the genes required for Myf5 and MyoD expression in arch core mesoderm, Tbx1, Capsulin and Pitx2 are those expressed earliest in branchiomeric muscle progenitor cells and are also expressed in cardiac progenitor cells [1,2,26,33]. These cells, lying immediately adjacent to skeletal muscle progenitor cells, are termed the second heart field and give rise to much of the heart by adding newly differentiated cells to the poles of the heart tube during cardiac looping [34,35]. The second heart field gives rise to all parts of the heart formed subsequent to the linear heart tube stage, the latter being derived from the cardiac crescent [34,35]. Embryological studies have long noted that the heart primordium forms from lateral cranial splanchnic mesoderm initially positioned ventral to the future face [3,8]. As the bilateral pharyngeal arches form in an anterior to posterior progression the connection between the arterial pole of the heart and the head moves caudally, sequential arch artery connections shifting from the first to the third to sixth arches [8]. The initial proximity between the head and heart is thus disguised in the definitive configuration, when the heart lies in the thoracic cavity [8]. Cells of the second heart field are contiguous medially to cells giving rise to the linear heart tube and characterized by the defining properties of differentiation delay and continuing proliferation [35]. Branchiomeric skeletal muscles derive from contiguous cranial mesoderm situated even more medially than cells of the second heart field. Perturbation of second heart field development results in conotruncal congenital heart defects. Striking examples include the truncus (single ventricular outlet) and tetralogy of Fallot (hypoplastic right ventricular outlet and a failure of formation of an independent left ventricular outlet) observed in DiGeorge (del22q11.2) syndrome patients haploinsufficient for TBX1 [36]. DiGeorge patients also have craniofacial defects including pharyngeal muscle weakness and this syndrome is a paradigm of a cardiocraniofacial developmental syndrome [3,36]. Tbx1 null mice fail not only to robustly activate branchiomeric myogenesis but also
to add sufficient second heart field derived cells to the elongating arterial pole of the heart tube due to proliferative impairment and precocious differentiation, resulting ultimately in a single ventricular outlet [37]. Tbx1, together with Pitx2 and Capsulin among other genes expressed in cranial mesoderm, may thus play pro-proliferative and anti-differentiation roles and promote second heart field deployment during pharyngeal morphogenesis [33]. These results have led to a model by which branchiomeric skeletal muscles and second heart field derived regions of the heart are divergent myogenic derivatives arising within a continuum of pharyngeal mesoderm (Fig. 2B; [1,2]). Major support for such a model has come from experimental embryology using the chick embryo where both cranial and splanchnic mesoderm have been shown to contribute to both head muscle primordia and the outflow tract of the heart [11,26]. A key gene in the early pharyngeal mesoderm genetic program encodes the LIM homeodomain transcription factor Isl1 [38]. Isl1 has been shown to identify multipotential cardiac progenitor cells in the early embryo and differentiating embryonic stem cells that can give rise to myocardial, endothelial and smooth muscle descendants [38]. This gene is also expressed in branchiomeric skeletal myogenic progenitor cells and is downregulated on differentiation to either cardiac or skeletal muscle fates [11]; indeed Isl1 misexpression in the chick leads to impaired skeletal myogenesis [5,11]. Use of an Isl1 Cre allele has confirmed that, within the heart, many cells originate from Isl1 positive progenitor cells, although only a small number express Isl1 itself [39]. Using a similar approach, the group of Tzahor has shown that branchiomeric skeletal muscles, apparently exactly the same subset of craniofacial muscles as those defined by Tbx1-requirement, originate from Isl1 expressing progenitor cells (Fig. 2A; [11]). Isl1 may thus act at a nodal point in differentiation and lineage specification of both cardiac and skeletal myogenic progenitor cells in pharyngeal mesoderm. Intriguingly the dynamic continuum between cranial and splanchnic mesoderm along the proximodistal axis of the arch is reflected in the properties of the definitive muscles derived from proximal and distal regions of the arch. Proximally, jaw closing muscles such as the masseter appear to have less Isl1 Cre labeled muscle fibers, although almost all satellite cells in this muscle are derived form Isl1 expressing progenitor cells (see below). This may reflect a reduced splanchnic contribution to these muscle primordia or a more transient expression of Isl1, as has been proposed for non-Isl1 Cre labeled regions of the heart [38]. Other differences between proximal and distal regions of the arch include engrailed2 expression, Capsulin/ MyoR dependence and a heterogeneous pathophysiological dystrophic response [16,27,40]. Defining the precise embryological relationship between core mesoderm and splanchnic mesoderm within this dynamic continuum remains an important question.
New insights into the origins and properties of branchiomeric satellite cells In a recent study the Tzahor group have extended their analysis to examine the origin of satellite cells in branchiomeric muscles [5]. Satellite cells are resident skeletal muscle stem cells positioned under the basal lamina of muscle fibers that contribute to muscle repair on damage and disease by differentiation and fusion [41]. The origin of satellite cells in somite derived muscles has been shown to be the epithelial somite [13]; Harel et al. [5] confirm this and show using Cre lineage analysis that satellite cells in all somite-derived
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muscles, including muscles of the tongue, have expressed the transcription factor Pax3. In contrast, satellite cells in branchiomeric muscles are unlabelled by a Pax3 Cre allele but are labeled by Isl1 Cre, including 90% of satellite cells in the masseter. This demonstrates that satellite cells share the developmental origin of their associated muscles, a point of considerable clinical relevance for myoblast treatment of muscle-restricted myopathies. Whereas the myogenic program in craniofacial and trunk muscles appears to largely converge after activation of the myogenic regulatory factor genes, marked differences remain, for example the masseter is characterized by specific myosin heavy chain gene expression profiles, elevated expression of stress–response genes and reduced fiber diameter [4,42]. Significant transcriptional differences are also observed between satellite cells, and their derived myoblasts, from branchiomeric versus somite-derived muscles, including 100-fold higher levels of Capsulin expression, while other genes such as Pax7 are expressed in all satellite cells [5–7]. Satellite cells thus retain the genetic signature of their muscle of origin. This is reflected in the distinct properties of satellite cells associated with branchiomeric and trunk derived muscles [7]. Although a spectrum of individual cell properties is observed in all muscles analyzed, satellite cells from the masseter tend to be fewer in number and to be more proliferative and have delayed differentiation compared to those from somite-derived muscles such as the extensor digitorum longus. These features may be associated with the impaired regenerative properties of certain branchiomeric muscles and elevated fast fiber numbers on ageing [40]. Challenging the differentiation program of branchiomeric satellite cells by transplantation experiments has shown that they retain the capacity to differentiate in the environment of somitederived muscles, with equivalent properties to satellite cells isolated from somite-derived muscles, although results differ in the extent to which transplanted cells differentiate with the full muscle of origin program [5,7]. Treatment of satellite cells with BMP increases Myf5 and Pax7 expression and blocks differentiation; in branchiomeric but not somite-derived satellite cells BMP treatment also activates cardiac gene expression including Isl1 and Tbx20. This result suggests that satellite cells retain the differential response to surrounding cues of their embryonic progenitor cells, of relevance for studies aimed at developing the use of skeletal myoblasts for cardiac repair [5]. Whether Isl1 is actively expressed in branchiomeric satellite cells and its potential role in the stem cell properties of these cells remains to be seen. Interestingly, while no equivalent population to satellite cells is found in cardiac muscle, a small number of residual Isl1 positive cells have been identified and proposed to be resident progenitor cells that may contribute to cardiac growth and repair in the fetal and early postnatal heart [38].
Evolutionary considerations The common origin of branchiomeric skeletal muscles and second heart field derived cells in pharyngeal mesoderm raises a number of important evolutionary issues. Much of what is known about the molecular regulation of skeletal myogenesis stems from studies of somite-derived muscles and branchiomeric myogenesis has been considered an “alien” system that developed with the evolution of the vertebrate head [43]. However the importance of muscular regulation of feeding and breathing suggests that the evolution of branchiomeric muscles may predate that of somite-derived muscles.
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Indeed in the sea urchin skeletal muscles are associated with endoderm and required for oesophageal function and operation of the feeding apparatus [44]. Of note, the sea urchin lacks a heart, suggesting a fluctuating distribution of pharyngeal mesodermal progenitor cells to skeletal versus cardiac myogenic fates over evolution. In Caenorhabditis elegans, similarly, there is no heart but rhythmically contracting skeletal myocytes regulate pharyngeal contraction and food intake that share properties with cardiac myocytes including expression of the C. elegans homologue of the cardiac transcription factor Nkx2.5 [45]. A common developmental and evolutionary program may thus underpin cardiac and pharyngeal myogenesis of relevance for dissecting the core circuitry regulating craniofacial myogenesis in higher vertebrates. Finally, within the vertebrates a great variety of branchiomeric muscle patterning is observed, associated with divergent craniofacial anatomy, likely reflecting the different strategies underlying niche diversification during vertebrate radiation [32]. The developmental importance of cranial neural crest cells during craniofacial skeletal muscle development has long been apparent [4]. Neural crest derived cells give rise to fascia and tendons associated with craniofacial muscles but not to skeletal myocytes themselves. Recent findings have ruled out a role for neural crest cells in the initiation of the skeletal myogenic program but shown that crest plays a critical role at all subsequent steps of branchiomeric muscle development, including patterning, muscle individualization, migration and differentiation [46,47]. While evolutionary modulation of the definitive branchiomeric musculature is thus likely to be the result of plasticity mediated by crest-associated changes that drive distinct facial morphologies, a role for mesoderm driven changes which can impact on development of associated structures such as mandible size and shape, as observed in Tbx1 mutant and Myf5 MyoD double mutant embryos, needs to be considered [19,48].
Perspectives The common origin of branchiomeric skeletal muscle and second heart field derived cardiomyocytes in pharyngeal mesoderm has led to exciting new insights into craniofacial myogenesis. Many important questions remain. Does this common origin reflect the existence of adjacent progenitor cell populations in a continuum of cranial mesoderm or are bipotential progenitor cells present in the mesodermal core of the arches? Do genes such as Tbx1 operative in both the second heart field and branchiomeric myogenesis play the same roles in both populations? How do the roles of Pitx2, Tbx1, Capsulin/MyoR and Isl1 converge on Myf5 and MyoD activation? How does this nascent gene regulatory network respond to intercellular signaling in the developing arches? Finally, how are muscle identity and pathologies associated with specific muscle groups linked to the diverse subprograms operating in different arches and arch subregions? Addressing these questions will provide new directions to both fundamental and clinically applied studies of cardiocraniofacial development.
Acknowledgments The author would like to thank Eldad Tzahor for Fig. 2A (right panel) and comments on the manuscript. RK is an Inserm research scientist and acknowledges the support of the Association
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Française contre les Myopathies, the Agence National pour la Recherche (ANR-007-MRAR-003), the Fondation pour la Recherche Médicale and the European Commission under the FP7 CardioGeNet project (Grant No. HEALTH-2007-B-223463).
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[18] F. Dong, X. Sun, W. Liu, D. Ai, E. Klysik, M.F. Lu, J. Hadley, L. Antoni, L. Chen, A. Baldini, P. Francis-West, J.F. Martin, Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle, Development (Cambridge, England) 133 (2006) 4891–4899. [19] R.G. Kelly, L.A. Jerome-Majewska, V.E. Papaioannou, The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis, Hum. Mol. Genet. 13 (2004) 2829–2840. [20] A. Dastjerdi, L. Robson, R. Walker, J. Hadley, Z. Zhang, M. Rodriguez-Niedenfuhr, P. Ataliotis, A. Baldini, P. Scambler, P. Francis-West, Tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm, Dev. Dyn. 236 (2007) 353–363. [21] R. Grifone, T. Jarry, M. Dandonneau, J. Grenier, D. Duprez, R.G. Kelly, Properties of branchiomeric and somite-derived muscle development in Tbx1 mutant embryos, Dev. Dyn. 237 (2008) 3071–3078. [22] J. Okano, Y. Sakai, K. Shiota, Retinoic acid down-regulates Tbx1 expression and induces abnormal differentiation of tongue muscles in fetal mice, Dev. Dyn. 237 (2008) 3059–3070. [23] E. Tzahor, H. Kempf, R.C. Mootoosamy, A.C. Poon, A. Abzhanov, C.J. Tabin, S. Dietrich, A.B. Lassar, Antagonists of Wnt and BMP signaling promote the formation of vertebrate head muscle, Genes Dev. 17 (2003) 3087–3099. [24] E. Tzahor, Wnt/beta-catenin signaling and cardiogenesis: timing does matter, Dev. Cell 13 (2007) 10–13. [25] K.L. Waldo, D.H. Kumiski, K.T. Wallis, H.A. Stadt, M.R. Hutson, D.H. Platt, M.L. Kirby, Conotruncal myocardium arises from a secondary heart field, Development (Cambridge, England) 128 (2001) 3179–3188. [26] L. Tirosh-Finkel, H. Elhanany, A. Rinon, E. Tzahor, Mesoderm progenitor cells of common origin contribute to the head musculature and the cardiac outflow tract, Development (Cambridge, England) 133 (2006) 1943–1953. [27] R.D. Knight, K. Mebus, H.H. Roehl, Mandibular arch muscle identity is regulated by a conserved molecular process during vertebrate development, J. Exp. Zool. 310 (2008) 355–369. [28] G. von Scheven, L.E. Alvares, R.C. Mootoosamy, S. Dietrich, Neural tube derived signals and Fgf8 act antagonistically to specify eye versus mandibular arch muscles, Development (Cambridge, England) 133 (2006) 2731–2745. [29] C.Y. Lin, R.F. Yung, H.C. Lee, W.T. Chen, Y.H. Chen, H.J. Tsai, Myogenic regulatory factors Myf5 and Myod function distinctly during craniofacial myogenesis of zebrafish, Dev. Biol. 299 (2006) 594–608. [30] C.Y. Lin, W.T. Chen, H.C. Lee, P.H. Yang, H.J. Yang, H.J. Tsai, The transcription factor Six1a plays an essential role in the craniofacial myogenesis of zebrafish, Dev. Biol. 331 (2009) 152–166. [31] R. Grifone, J. Demignon, C. Houbron, E. Souil, C. Niro, M.J. Seller, G. Hamard, P. Maire, Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo, Development (Cambridge, England) 132 (2005) 2235–2249. [32] A.S. Romer, T.S. Parsons, The vertebrate body 4th edition, Saunder's College Publishing, 1977. [33] I. Bothe, S. Dietrich, The molecular setup of the avian head mesoderm and its implication for craniofacial myogenesis, Dev. Dyn. 235 (2006) 2845–2860. [34] M. Buckingham, S. Meilhac, S. Zaffran, Building the mammalian heart from two sources of myocardial cells, Nat. Rev 6 (2005) 826–835. [35] F. Rochais, K. Mesbah, R.G. Kelly, Signaling pathways controlling second heart field development, Circ. Res. 104 (2009) 933–942. [36] A. Baldini, Dissecting contiguous gene defects: TBX1, Curr. Opin. Genet. Dev. 15 (2005) 279–284. [37] L. Chen, F.G. Fulcoli, S. Tang, A. Baldini, Tbx1 regulates proliferation and differentiation of multipotent heart progenitors, Circ. Res. 105 (2009) 842–851. [38] K.L. Laugwitz, A. Moretti, L. Caron, A. Nakano, K.R. Chien, Islet1 cardiovascular progenitors: a single source for heart lineages? Development (Cambridge, England) 135 (2008) 193–205.
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available at www.sciencedirect.com
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Review
Core issues in craniofacial myogenesis Robert G. Kelly⁎ Developmental Biology Institute of Marseilles-Luminy, UMR6216 CNRS Université de la Méditerranée, Campus de Luminy Case 907, 13288 Marseille Cedex 9 France
A R T I C L E I N F O R M A T I O N
A B S T R A C T
Article Chronology:
Branchiomeric craniofacial muscles control feeding, breathing and facial expression. These
Received 1 March 2010
muscles differ on multiple counts from all other skeletal muscles and originate in a progenitor cell
Revised version received 23 April 2010
population in pharyngeal mesoderm characterized by a common genetic program with an
Accepted 28 April 2010
adjacent population of cardiac progenitor cells, the second heart field, that gives rise to much of the
Available online 8 May 2010
heart. The transcription factors and signaling molecules that trigger the myogenic program at sites of branchiomeric muscle formation are correspondingly distinct from those in somite-derived
Keywords:
muscle progenitor cells. Here new insights into the regulatory hierarchies controlling
Skeletal muscle
branchiomeric myogenesis are discussed. Differences in embryological origin are reflected in
Craniofacial development
the lineage, transcriptional program and proliferative and differentiation properties of
Tbx1
branchiomeric muscle satellite cells. These recent findings have important implications for our
Heart development
understanding of the diverse myogenic strategies operative both in the embryo and adult and are of direct biomedical relevance to deciphering the mechanisms underlying the cause and progression of muscle restricted myopathies. © 2010 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulatory networks controlling branchiomeric myogenesis . . . . . . Reinforcing links between heart and head muscle development . . . . New insights into the origins and properties of branchiomeric satellite Evolutionary considerations . . . . . . . . . . . . . . . . . . . . . . . Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Branchiomeric craniofacial skeletal muscles are involved in feeding, breathing and facial expression, rather than locomotion, and
⁎ Fax: +33 491269726. E-mail address: [email protected]. 0014-4827/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yexcr.2010.04.029
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originate from cranial mesoderm in the core of the bilateral branchial (or pharyngeal) arches. The progenitor cell populations that give rise to these muscles have recently been shown to share the genetic signature of an adjacent population of pharyngeal mesodermal cells
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that contribute to myocardium at the poles of the heart tube during cardiac looping, a progenitor cell population termed the second heart field [1,2]. This observation highlights the visceral nature of branchiomeric skeletal muscles which thus differ fundamentally from all other skeletal muscles in the embryo that are derived from somites (trunk, limb, ventral pharyngeal and tongue muscles) or prechordal mesoderm (extraocular muscles). Furthermore, the two myogenic fates of pharyngeal mesoderm provide additional evidence for a cardiocraniofacial field underlying normal and pathological head and heart development [3]. Here recent embryological and molecular insights into the regulation of branchiomeric myogenesis, together with new findings as to the origins and properties of branchiomeric muscle satellite cells will be reviewed. These data consolidate and expand our understanding of the mechanisms regulating common and divergent features of head and heart muscle development and provide a framework for deciphering mechanisms underlying the origin and progression of muscle restricted myopathies. A number of recent reviews have detailed the multiple points distinguishing branchiomeric craniofacial muscles from other skeletal muscles in the embryo [1,2,4]. These include embryonic origin, in cranial mesoderm rather then somites; function, in feeding, breathing and facial expression rather than locomotion; motor innervation, branchiomeric motor neurons having visceral rather than somatic motor columns; the cis and trans regulation of the genes encoding the myogenic determination factors Myf5 and MyoD. In the last year several papers have shown that despite an apparent convergence of branchiomeric skeletal muscles with the skeletal muscle program of all other muscles after activation of these myogenic determination genes, certain distinguishing features remain. In particular, these concern branchiomeric skeletal muscle stem cells or satellite cells, that reflect their origin in pharyngeal cranial mesoderm and the common history with their developmental neighbors, cardiac progenitor cells of the second heart field [5–7]. Before discussing these new papers, we will consider the embryology and molecular regulation of branchiomeric muscles. Initiation of the myogenic program occurs in the mesodermal core of each of the five bilateral branchial arches, each comprised of pharyngeal epithelia, ectoderm and endoderm, surrounding a neural crestderived mesenchymal cell population and a central relatively compact mesodermal core (Fig. 1A; [8]). Importantly for this review, each arch also contains an artery connecting the arterial pole of the heart to the descending aorta. The first branchial arch will form the mandible of jawed vertebrates; whereas in fish the posterior branchial arches are maintained as gills, in amniotes they are transient structures that during subsequent development give rise to components of the face and neck. The arch arteries are remodeled to generate arteries of the head and the great vessels connecting the definitive ventricular outlets to the descending aorta and pulmonary arteries [8].
Regulatory networks controlling branchiomeric myogenesis The colonization of the arches by core mesoderm is thought to occur by lateral movement of preotic cranial mesoderm with a splanchnic mesodermal contribution in the distal region of the arch [4,9–11]. However, unlike mesoderm at the level of the somites, cranial mesoderm is not morphologically divided into paraxial, intermedi-
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ate and lateral domains and proximodistal patterning of core arch mesoderm appears to reflect a dynamic continuum along the medial–lateral embryonic axis (Fig. 1A). Myf5 and MyoD are known to be the two key regulatory factors driving determination of branchiomeric myogenesis within core arch mesoderm and in their absence craniofacial myogenesis fails, whereas trunk muscle development is rescued by Mrf4 [12,13]. The enhancers driving Myf5 activation in the arches are dispersed over a large upstream region of the gene and include elements operating in specific arches, an illustration of the fact that branchiomeric myogenesis in turn represents a composite of subprograms and myogenic strategies operating in different regions of the arches and in different arches themselves [14]. The transcription factors known to operate upstream of Myf5 and MyoD in branchiomeric muscle development also differ from those identified in developing somites. The paired homeoprotein Pax3 is expressed in developing somites but not sites of branchiomeric muscle development; trunk and limb myogenesis, but not head muscle development, fails in Pax3 Myf5 double mutant embryos, Pax3 being required for Myf5-independent MyoD activation in somite-derived muscles [15]. In contrast, four transcription factors have been identified that play specific roles in branchiomeric myogenesis. Capsulin (Tcf21) and MyoR, two bHLH transcriptional repressors, are together required for Myf5 activation in the mandibular arch and in double mutant embryos cell death is elevated in core mesoderm resulting in a failure to develop jaw closing muscles derived from the proximal first arch [16]. Pitx2, a homeobox transcription factor, is required for extraocular muscle development in prechordal mesoderm and differentiation and survival of myogenic progenitors in the first arch [17,18]. The Tbox containing transcriptional activator Tbx1 regulates robust bilateral activation of Myf5 and MyoD in all branchiomeric muscles, defining a subset of craniofacial muscles as Tbx1-dependent branchiomeric muscles, including laryngeal muscles and the cervical component of the trapezius muscle (Fig. 1B; [19–21]). Differentiation of extraocular muscles and tongue musculature is Tbx1 independent, although intriguingly developing tongue muscles express Tbx1 [22]. Stochastic activation of myogenesis in the absence of Tbx1 results in the formation of hypoplastic, frequently unilateral skeletal muscles that appear to have normal patterning and to be colonized by Pax7 positive cells with normal proliferative and differentiation capacities (Fig. 2A; [21]). Tbx1 is thus not absolutely required for the activation of branchiomeric myogenesis but rather ensures that the specification step occurs robustly; once this early requirement for Tbx1 is bypassed normal myogenesis ensues [19,21]. Arches 2–6 are extremely hypoplastic in Tbx1 null embryos, reflecting the fact that this gene plays additional upstream roles in pharyngeal morphogenesis. The molecular mechanisms by which these four transcription factors regulate branchiomeric myogenesis, including identification of direct targets and potential interactions, remain unknown. The mesodermal core of the branchial arches is exposed to a variety of intercellular signals, emanating from pharyngeal epithelia, neural crest cells and autocrine sources. Intercellular signaling pathways differ in their impact on the myogenic program in the head and trunk [1,2,4]. Interest has focused on Wnt, bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signaling in regulating early events of branchiomeric myogenesis. Wnt signaling appears to be important in maintaining the progenitor cell state in pharyngeal mesoderm and delaying myogenic differentiation [11,23,24]. Intriguingly, delayed differentiation after activation of
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Fig. 1 – Branchiomeric craniofacial myogenesis. (A) Left: cartoon contrasting cranial and trunk mesoderm in the early embryo; middle: MyoD transcript distribution at midgestation in sites of somite-derived and branchiomeric myogenesis; right: schematic sections though the early head region and branchial arch region corresponding to the dashed lines i and ii. P and D indicate the proximodistal arch axis. (B) Left lateral, dorsal and submandibular views of embryos showing MyoD transcript distribution and Myf5-nlacZ transgene expression. Note the loss of branchiomeric craniofacial muscles in Tbx1 mutant embryos including mandibular muscles (m), muscles of facial expression (f), muscles of the larynx, pharynx (p) and the cervical trapezius (arrowhead) but not tongue muscles (t). The genetic dissection of a subset of craniofacial muscles observed in the absence of Tbx1 is comparable to sequential dissection of neck muscles in a human cadaver. Adapted with permission from references [1], [19] and [49].
myogenic determination genes is another distinction between branchiomeric and somite-derived myogenesis, potentially linked with the need to correctly position the primordia of jaw operating and facial expression muscles during morphogenesis of the head.
BMP signaling has been proposed to drive the cardiac differentiation program in distal arch mesoderm during heart tube elongation, while FGF signaling promotes cardiac progenitor cell proliferation [5,25,26]. A recent study in the zebrafish has found that FGF, but not
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Fig. 2 – The pharyngeal myogenic lineage. (A) Comparison of Tbx1 dependent and Isl1 lineage derived craniofacial muscles. Branchiomeric but not extraocular (eom) or tongue (t) muscles are Tbx1-dependent and derived from Isl1 expressing progenitor cells. Note the sporadic hypoplastic right masseter (asterisk), facial expression (arrowhead) and anterior digastric muscles in the Tbx1 mutant embryo labeled by a Myf5-nlacZ transgene. Almost all muscles of facial expression and the left masseter are absent; affected muscles correspond to those expressing β-galactosidase activated by Isl1-Cre. (B) Cartoon showing the contribution of pharyngeal mesoderm to branchiomeric skeletal muscles and second heart field derived components of the heart. The remainder of the heart is derived from lateral splanchnic mesoderm and other skeletal muscles are derived from somites (trunk, limb, ventral pharyngeal and tongue muscles) or prechordal cranial mesoderm (extraocular muscles). The properties of somitic and branchiomeric muscle satellite cells reflect the origin of their associated muscles. Adapted with permission from references [1] and [11]. Notch, Hedgehog or BMP signaling, is required for activation of engrailed2, encoding a homeodomain transcription factor, in the dorsal first arch, a readout likely reflecting patterning of core mesoderm in the first arch [27]. Expression of engrailed2 was also found to be dependent on the fish homologue of Tbx1, vgo, although Tbx1, as well as Capsulin expression, was unaltered in embryos cultured in the presence of FGF signaling pathway inhibitors. These experiments also found that FGF signaling is continuously required to maintain the branchiomeric myogenic program after specification [27]. The expression of certain FGF ligand and receptor encoding genes is known to be Tbx1dependent in the mouse, suggesting that FGF signaling may act downstream of Tbx1 function, although analysis of ace zebrafish mutants (lacking Fgf8) and Fgf10 null mouse embryos has shown that these ligands are not individually required for the activation of branchiomeric myogenesis [19,27]. Fgf8, however, appears to play a role in promoting branchiomeric over extraocular myogenesis, potentially polarizing the proximodistal axis of the arch [28]. The zebrafish study also ruled out a major role for signals from the neural tube or pharyngeal endoderm in the activation of engrailed2 expression, consistent with studies in chick embryos and suggesting that the
specification of branchiomeric muscles is a highly robust and potentially cell-autonomous process [27,28]. A detailed genetic analysis in the mouse has yielded important insight into the regulatory hierarchies in branchiomeric muscle development, as well as fundamental insights into the hierarchies regulating extraocular muscle development beyond the scope of this short review [6]. Analysis of embryos doubly mutant for Tbx1 and Myf5 revealed that the stochastic formation of hypoplastic muscles observed in Tbx1 null embryos was severely impaired, although not completely abolished, in the absence of both genes [6]. This reveals that Myf5 must be required for most of the residual myogenesis occurring in Tbx1 mutant embryos and furthermore that the activation of MyoD that normally rescues craniofacial myogenesis in Myf5 mutant embryos must be Tbx1 driven [6,12]. Thus Tbx1 sits upstream of MyoD in the branchiomeric myogenic hierarchy, in a similar position to Pax3 in trunk myogenesis. Given that Tbx1 also regulates Myf5, Tbx1 is likely to be situated in an outer layer of the regulatory circuit surrounding the core myogenic program in head myogenesis [6]. Analysis of craniofacial myogenesis in the zebrafish has revealed that the functions of Myf5 and MyoD are non-redundant during branchiomeric muscle development and has implicated the homeodomain transcription factor Six1 in the maintenance of the
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branchiomeric myogenic program [29,30]. Six1 is activated after Myf5 during branchiomeric myogenesis and appears to be independent of the Tbx1 pathway, also playing a Pax3-like role upstream of MyoD in branchiomeric muscle differentiation [30]. This study also provides genetic evidence that Tbx1 directly activates Myf5, since Myf5 cDNA, but not that of MyoD or Six1, rescued myogenesis after Tbx1 knockdown [30]. Six1, together with Six4, is required for formation of certain muscles in the mouse, although a specific role in branchiomeric myogenesis has not been observed [31].
Reinforcing links between heart and head muscle development The contribution of mesoderm associated with the gut to head musculature was noted by Romer who highlighted the visceral nature of branchiomeric skeletal muscles: “branchial and gut muscles, striated or smooth, are but the anterior and posterior parts of a single great visceral system of muscles whose primary locus is in the walls of the digestive tract” [32]. Molecular genetic analysis now largely corroborates this visceral view of branchiomeric myogenesis and supports the hypothesis of a common developmental and evolutionary origin with another myogenic derivative of visceral mesoderm, myocardium. Indeed, recent data has demonstrated that pharyngeal mesoderm gives rise not only to branchiomeric skeletal muscles but also to part of the heart. Among the genes required for Myf5 and MyoD expression in arch core mesoderm, Tbx1, Capsulin and Pitx2 are those expressed earliest in branchiomeric muscle progenitor cells and are also expressed in cardiac progenitor cells [1,2,26,33]. These cells, lying immediately adjacent to skeletal muscle progenitor cells, are termed the second heart field and give rise to much of the heart by adding newly differentiated cells to the poles of the heart tube during cardiac looping [34,35]. The second heart field gives rise to all parts of the heart formed subsequent to the linear heart tube stage, the latter being derived from the cardiac crescent [34,35]. Embryological studies have long noted that the heart primordium forms from lateral cranial splanchnic mesoderm initially positioned ventral to the future face [3,8]. As the bilateral pharyngeal arches form in an anterior to posterior progression the connection between the arterial pole of the heart and the head moves caudally, sequential arch artery connections shifting from the first to the third to sixth arches [8]. The initial proximity between the head and heart is thus disguised in the definitive configuration, when the heart lies in the thoracic cavity [8]. Cells of the second heart field are contiguous medially to cells giving rise to the linear heart tube and characterized by the defining properties of differentiation delay and continuing proliferation [35]. Branchiomeric skeletal muscles derive from contiguous cranial mesoderm situated even more medially than cells of the second heart field. Perturbation of second heart field development results in conotruncal congenital heart defects. Striking examples include the truncus (single ventricular outlet) and tetralogy of Fallot (hypoplastic right ventricular outlet and a failure of formation of an independent left ventricular outlet) observed in DiGeorge (del22q11.2) syndrome patients haploinsufficient for TBX1 [36]. DiGeorge patients also have craniofacial defects including pharyngeal muscle weakness and this syndrome is a paradigm of a cardiocraniofacial developmental syndrome [3,36]. Tbx1 null mice fail not only to robustly activate branchiomeric myogenesis but also
to add sufficient second heart field derived cells to the elongating arterial pole of the heart tube due to proliferative impairment and precocious differentiation, resulting ultimately in a single ventricular outlet [37]. Tbx1, together with Pitx2 and Capsulin among other genes expressed in cranial mesoderm, may thus play pro-proliferative and anti-differentiation roles and promote second heart field deployment during pharyngeal morphogenesis [33]. These results have led to a model by which branchiomeric skeletal muscles and second heart field derived regions of the heart are divergent myogenic derivatives arising within a continuum of pharyngeal mesoderm (Fig. 2B; [1,2]). Major support for such a model has come from experimental embryology using the chick embryo where both cranial and splanchnic mesoderm have been shown to contribute to both head muscle primordia and the outflow tract of the heart [11,26]. A key gene in the early pharyngeal mesoderm genetic program encodes the LIM homeodomain transcription factor Isl1 [38]. Isl1 has been shown to identify multipotential cardiac progenitor cells in the early embryo and differentiating embryonic stem cells that can give rise to myocardial, endothelial and smooth muscle descendants [38]. This gene is also expressed in branchiomeric skeletal myogenic progenitor cells and is downregulated on differentiation to either cardiac or skeletal muscle fates [11]; indeed Isl1 misexpression in the chick leads to impaired skeletal myogenesis [5,11]. Use of an Isl1 Cre allele has confirmed that, within the heart, many cells originate from Isl1 positive progenitor cells, although only a small number express Isl1 itself [39]. Using a similar approach, the group of Tzahor has shown that branchiomeric skeletal muscles, apparently exactly the same subset of craniofacial muscles as those defined by Tbx1-requirement, originate from Isl1 expressing progenitor cells (Fig. 2A; [11]). Isl1 may thus act at a nodal point in differentiation and lineage specification of both cardiac and skeletal myogenic progenitor cells in pharyngeal mesoderm. Intriguingly the dynamic continuum between cranial and splanchnic mesoderm along the proximodistal axis of the arch is reflected in the properties of the definitive muscles derived from proximal and distal regions of the arch. Proximally, jaw closing muscles such as the masseter appear to have less Isl1 Cre labeled muscle fibers, although almost all satellite cells in this muscle are derived form Isl1 expressing progenitor cells (see below). This may reflect a reduced splanchnic contribution to these muscle primordia or a more transient expression of Isl1, as has been proposed for non-Isl1 Cre labeled regions of the heart [38]. Other differences between proximal and distal regions of the arch include engrailed2 expression, Capsulin/ MyoR dependence and a heterogeneous pathophysiological dystrophic response [16,27,40]. Defining the precise embryological relationship between core mesoderm and splanchnic mesoderm within this dynamic continuum remains an important question.
New insights into the origins and properties of branchiomeric satellite cells In a recent study the Tzahor group have extended their analysis to examine the origin of satellite cells in branchiomeric muscles [5]. Satellite cells are resident skeletal muscle stem cells positioned under the basal lamina of muscle fibers that contribute to muscle repair on damage and disease by differentiation and fusion [41]. The origin of satellite cells in somite derived muscles has been shown to be the epithelial somite [13]; Harel et al. [5] confirm this and show using Cre lineage analysis that satellite cells in all somite-derived
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muscles, including muscles of the tongue, have expressed the transcription factor Pax3. In contrast, satellite cells in branchiomeric muscles are unlabelled by a Pax3 Cre allele but are labeled by Isl1 Cre, including 90% of satellite cells in the masseter. This demonstrates that satellite cells share the developmental origin of their associated muscles, a point of considerable clinical relevance for myoblast treatment of muscle-restricted myopathies. Whereas the myogenic program in craniofacial and trunk muscles appears to largely converge after activation of the myogenic regulatory factor genes, marked differences remain, for example the masseter is characterized by specific myosin heavy chain gene expression profiles, elevated expression of stress–response genes and reduced fiber diameter [4,42]. Significant transcriptional differences are also observed between satellite cells, and their derived myoblasts, from branchiomeric versus somite-derived muscles, including 100-fold higher levels of Capsulin expression, while other genes such as Pax7 are expressed in all satellite cells [5–7]. Satellite cells thus retain the genetic signature of their muscle of origin. This is reflected in the distinct properties of satellite cells associated with branchiomeric and trunk derived muscles [7]. Although a spectrum of individual cell properties is observed in all muscles analyzed, satellite cells from the masseter tend to be fewer in number and to be more proliferative and have delayed differentiation compared to those from somite-derived muscles such as the extensor digitorum longus. These features may be associated with the impaired regenerative properties of certain branchiomeric muscles and elevated fast fiber numbers on ageing [40]. Challenging the differentiation program of branchiomeric satellite cells by transplantation experiments has shown that they retain the capacity to differentiate in the environment of somitederived muscles, with equivalent properties to satellite cells isolated from somite-derived muscles, although results differ in the extent to which transplanted cells differentiate with the full muscle of origin program [5,7]. Treatment of satellite cells with BMP increases Myf5 and Pax7 expression and blocks differentiation; in branchiomeric but not somite-derived satellite cells BMP treatment also activates cardiac gene expression including Isl1 and Tbx20. This result suggests that satellite cells retain the differential response to surrounding cues of their embryonic progenitor cells, of relevance for studies aimed at developing the use of skeletal myoblasts for cardiac repair [5]. Whether Isl1 is actively expressed in branchiomeric satellite cells and its potential role in the stem cell properties of these cells remains to be seen. Interestingly, while no equivalent population to satellite cells is found in cardiac muscle, a small number of residual Isl1 positive cells have been identified and proposed to be resident progenitor cells that may contribute to cardiac growth and repair in the fetal and early postnatal heart [38].
Evolutionary considerations The common origin of branchiomeric skeletal muscles and second heart field derived cells in pharyngeal mesoderm raises a number of important evolutionary issues. Much of what is known about the molecular regulation of skeletal myogenesis stems from studies of somite-derived muscles and branchiomeric myogenesis has been considered an “alien” system that developed with the evolution of the vertebrate head [43]. However the importance of muscular regulation of feeding and breathing suggests that the evolution of branchiomeric muscles may predate that of somite-derived muscles.
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Indeed in the sea urchin skeletal muscles are associated with endoderm and required for oesophageal function and operation of the feeding apparatus [44]. Of note, the sea urchin lacks a heart, suggesting a fluctuating distribution of pharyngeal mesodermal progenitor cells to skeletal versus cardiac myogenic fates over evolution. In Caenorhabditis elegans, similarly, there is no heart but rhythmically contracting skeletal myocytes regulate pharyngeal contraction and food intake that share properties with cardiac myocytes including expression of the C. elegans homologue of the cardiac transcription factor Nkx2.5 [45]. A common developmental and evolutionary program may thus underpin cardiac and pharyngeal myogenesis of relevance for dissecting the core circuitry regulating craniofacial myogenesis in higher vertebrates. Finally, within the vertebrates a great variety of branchiomeric muscle patterning is observed, associated with divergent craniofacial anatomy, likely reflecting the different strategies underlying niche diversification during vertebrate radiation [32]. The developmental importance of cranial neural crest cells during craniofacial skeletal muscle development has long been apparent [4]. Neural crest derived cells give rise to fascia and tendons associated with craniofacial muscles but not to skeletal myocytes themselves. Recent findings have ruled out a role for neural crest cells in the initiation of the skeletal myogenic program but shown that crest plays a critical role at all subsequent steps of branchiomeric muscle development, including patterning, muscle individualization, migration and differentiation [46,47]. While evolutionary modulation of the definitive branchiomeric musculature is thus likely to be the result of plasticity mediated by crest-associated changes that drive distinct facial morphologies, a role for mesoderm driven changes which can impact on development of associated structures such as mandible size and shape, as observed in Tbx1 mutant and Myf5 MyoD double mutant embryos, needs to be considered [19,48].
Perspectives The common origin of branchiomeric skeletal muscle and second heart field derived cardiomyocytes in pharyngeal mesoderm has led to exciting new insights into craniofacial myogenesis. Many important questions remain. Does this common origin reflect the existence of adjacent progenitor cell populations in a continuum of cranial mesoderm or are bipotential progenitor cells present in the mesodermal core of the arches? Do genes such as Tbx1 operative in both the second heart field and branchiomeric myogenesis play the same roles in both populations? How do the roles of Pitx2, Tbx1, Capsulin/MyoR and Isl1 converge on Myf5 and MyoD activation? How does this nascent gene regulatory network respond to intercellular signaling in the developing arches? Finally, how are muscle identity and pathologies associated with specific muscle groups linked to the diverse subprograms operating in different arches and arch subregions? Addressing these questions will provide new directions to both fundamental and clinically applied studies of cardiocraniofacial development.
Acknowledgments The author would like to thank Eldad Tzahor for Fig. 2A (right panel) and comments on the manuscript. RK is an Inserm research scientist and acknowledges the support of the Association
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Française contre les Myopathies, the Agence National pour la Recherche (ANR-007-MRAR-003), the Fondation pour la Recherche Médicale and the European Commission under the FP7 CardioGeNet project (Grant No. HEALTH-2007-B-223463).
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