Distinct regulatory cascades govern extraocular and pharyngeal arch muscle progenitor cell fates.

Genetic regulatory networks governing skeletal myogenesis in the body are well understood, yet their hierarchical relationships in the head remain unresolved. We show that either Myf5 or Mrf4 is necessary for initiating extraocular myogenesis. Whereas Mrf4 is dispensable for pharyngeal muscle progenitor fate, Tbx1 and Myf5 act synergistically for governing myogenesis in this location. As in the body, Myod acts epistatically to the initiating cascades in the head. Thus, complementary pathways, governed by Pax3 for body, and Tbx1 for pharyngeal muscles, but absent for extraocular muscles, activate the core myogenic network. These diverse muscle progenitors maintain their respective embryonic regulatory signatures in the adult. However, these signatures are not sufficient to ensure the specific muscle phenotypes, since the expected differentiated phenotype is not manifested when satellite cells are engrafted heterotopically. These findings identify novel genetic networks that may provide insights into myopathies which often affect only subsets of muscles.

[1]  M. Rudnicki,et al.  Pax7 Is Required for the Specification of Myogenic Satellite Cells , 2000, Cell.

[2]  A. Abzhanov,et al.  Antagonists of Wnt and BMP signaling promote the formation of vertebrate head muscle. , 2003, Genes & development.

[3]  J. D. Di Santo,et al.  Dissecting NK cell development using a novel alymphoid mouse model: investigating the role of the c-abl proto-oncogene in murine NK cell differentiation. , 1999, Journal of immunology.

[4]  Thomas D. Schmittgen,et al.  Analyzing real-time PCR data by the comparative CT method , 2008, Nature Protocols.

[5]  N. L. Le Douarin,et al.  The developmental fate of the cephalic mesoderm in quail-chick chimeras. , 1992, Development.

[6]  D. Stacey.  Cyclin D1 serves as a cell cycle regulatory switch in actively proliferating cells. , 2003, Current opinion in cell biology.

[7]  V. Papaioannou,et al.  DiGeorge syndrome phenotype in mice mutant for the T-box gene, Tbx1 , 2001, Nature Genetics.

[8]  R. Kelly,et al.  Properties of branchiomeric and somite‐derived muscle development in Tbx1 mutant embryos , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[9]  G M Cohen,et al.  Caspases: the executioners of apoptosis. , 1997, The Biochemical journal.

[10]  A. Baldini,et al.  Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle , 2006, Development.

[11]  T. Braun,et al.  Inactivation of Myf‐6 and Myf‐5 genes in mice leads to alterations in skeletal muscle development. , 1995, The EMBO journal.

[12]  I. Harel,et al.  Distinct origins and genetic programs of head muscle satellite cells. , 2009, Developmental cell.

[13]  T. Borchardt,et al.  Different autonomous myogenic cell populations revealed by ablation of Myf5-expressing cells during mouse embryogenesis , 2008, Development.

[14]  J. Drouin,et al.  A Pituitary Cell-Restricted T Box Factor, Tpit, Activates POMC Transcription in Cooperation with Pitx Homeoproteins , 2001, Cell.

[15]  Philip Gage,et al.  Sequential expression and redundancy of Pitx2 and Pitx3 genes during muscle development. , 2007, Developmental biology.

[16]  L. Jerome-Majewska,et al.  The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis. , 2004, Human molecular genetics.

[17]  I. Harel,et al.  The contribution of Islet1-expressing splanchnic mesoderm cells to distinct branchiomeric muscles reveals significant heterogeneity in head muscle development , 2008, Development.

[18]  P. Francis-West,et al.  The differentiation and morphogenesis of craniofacial muscles , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[19]  S. Hughes,et al.  Myogenic and neurogenic regulation of myosin gene expression in cat jaw-closing muscles regenerating in fast and slow limb muscle beds , 1988, Journal of Muscle Research & Cell Motility.

[20]  A. English,et al.  Heterogeneity among muscle precursor cells in adult skeletal muscles with differing regenerative capacities , 1998, Developmental dynamics : an official publication of the American Association of Anatomists.

[21]  J. Stringer,et al.  Human placental alkaline phosphatase as a histochemical marker of gene expression in transgenic mice , 1996, Transgenic Research.

[22]  C. Kioussi,et al.  Cranial muscle defects of Pitx2 mutants result from specification defects in the first branchial arch , 2007, Proceedings of the National Academy of Sciences.

[23]  M. Rudnicki,et al.  Myf5 and MyoD activation define independent myogenic compartments during embryonic development. , 2003, Developmental biology.

[24]  A. Emery,et al.  The muscular dystrophies , 2002, The Lancet.

[25]  G. Cossu,et al.  Redefining the Genetic Hierarchies Controlling Skeletal Myogenesis: Pax-3 and Myf-5 Act Upstream of MyoD , 1997, Cell.

[26]  G. Cossu,et al.  Myosin light chain 3F regulatory sequences confer regionalized cardiac and skeletal muscle expression in transgenic mice , 1995, The Journal of cell biology.

[27]  G. Cann,et al.  Patterning of fast and slow fibers within embryonic muscles is established independently of signals from the surrounding mesenchyme. , 2001, Development.

[28]  C. Emerson,et al.  Myogenic regulatory factors and the specification of muscle progenitors in vertebrate embryos. , 2002, Annual review of cell and developmental biology.

[29]  S. Dietrich,et al.  Neural tube derived signals and Fgf8 act antagonistically to specify eye versus mandibular arch muscles , 2006, Development.

[30]  I. Nonaka,et al.  Myogenin gene disruption results in perinatal lethality because of severe muscle defect , 1993, Nature.

[31]  L. Thornell,et al.  Human extraocular muscles: unique pattern of myosin heavy chain expression during myotube formation. , 2000, Investigative ophthalmology & visual science.

[32]  G. Hamard,et al.  Six1 and Six4 homeoproteins are required for Pax3 and Mrf expression during myogenesis in the mouse embryo , 2005, Development.

[33]  S. Dietrich,et al.  The molecular setup of the avian head mesoderm and its implication for craniofacial myogenesis , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[34]  Z. Yablonka-Reuveni,et al.  The Skeletal Muscle Satellite Cell: The Stem Cell That Came in From the Cold , 2006, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[35]  R. Sambasivan,et al.  Skeletal muscle stem cell birth and properties. , 2007, Seminars in cell & developmental biology.

[36]  S. Hughes,et al.  Local signals in the chick limb bud can override myoblast lineage commitment: induction of slow myosin heavy chain in fast myoblasts , 1999, Mechanisms of Development.

[37]  Wei Zhang,et al.  Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies. , 1995, Genes & development.

[38]  A. Mansouri,et al.  A Pax3/Pax7-dependent population of skeletal muscle progenitor cells , 2005, Nature.

[39]  M. Rudnicki,et al.  Increased survival of muscle stem cells lacking the MyoD gene after transplantation into regenerating skeletal muscle , 2007, Proceedings of the National Academy of Sciences.

[40]  Roy C Mootoosamy,et al.  Distinct regulatory cascades for head and trunk myogenesis. , 2002, Development.

[41]  C. Laclef,et al.  Eya1 and Eya2 proteins are required for hypaxial somitic myogenesis in the mouse embryo. , 2007, Developmental biology.

[42]  S. Tajbakhsh,et al.  Muscle progenitor cells failing to respond to positional cues adopt non-myogenic fates in myf-5 null mice , 1996, Nature.

[43]  J. Hoh,et al.  Expression of extraocular myosin heavy chain in rabbit laryngeal muscle , 1995, Journal of Muscle Research & Cell Motility.

[44]  S. Guthrie,et al.  A distinct developmental programme for the cranial paraxial mesoderm in the chick embryo. , 1998, Development.

[45]  R. Marcucio,et al.  Differentiation of avian craniofacial muscles: I. Patterns of early regulatory gene expression and myosin heavy chain synthesis , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[46]  G. Cossu,et al.  How is myogenesis initiated in the embryo? , 1996, Trends in genetics : TIG.

[47]  B. Morrow,et al.  Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field , 2006, Development.

[48]  E. Hoffman,et al.  Definition of the unique human extraocular muscle allotype by expression profiling. , 2005, Physiological genomics.

[49]  S. Schiaffino,et al.  Fibre types in extraocular muscles: a new myosin isoform in the fast fibres , 1987, Journal of Muscle Research & Cell Motility.

[50]  S. Miyagawa-Tomita,et al.  Mouse Pitx2 deficiency leads to anomalies of the ventral body wall, heart, extra- and periocular mesoderm and right pulmonary isomerism. , 1999, Development.

[51]  R. Kelly,et al.  Heartening news for head muscle development. , 2007, Trends in genetics : TIG.

[52]  L. Silver,et al.  Expression of the T‐box family genes, Tbx1–Tbx5, during early mouse development , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[53]  H. Blau,et al.  Muscle fiber pattern is independent of cell lineage in postnatal rodent development , 1992, Cell.

[54]  Barbara Gayraud-Morel,et al.  A role for the myogenic determination gene Myf5 in adult regenerative myogenesis. , 2007, Developmental biology.

[55]  M. Rudnicki,et al.  MyoD or Myf-5 is required for the formation of skeletal muscle , 1993, Cell.

[56]  N. Copeland,et al.  A highly efficient recombineering-based method for generating conditional knockout mutations. , 2003, Genome research.

[57]  M. Capecchi,et al.  Two cell lineages, myf5 and myf5-independent, participate in mouse skeletal myogenesis. , 2008, Developmental cell.

[58]  Barbara Gayraud-Morel,et al.  Mrf4 determines skeletal muscle identity in Myf5:Myod double-mutant mice , 2004, Nature.

[59]  I. D'Agnano,et al.  MyoD induces apoptosis in the absence of RB function through a p21WAF1-dependent re-localization of cyclin/cdk complexes to the nucleus , 2002, Oncogene.

[60]  William H. Klein,et al.  Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene , 1993, Nature.

[61]  J. D. Porter.  Extraocular Muscle: Cellular Adaptations for a Diverse Functional Repertoire , 2002, Annals of the New York Academy of Sciences.

[62]  B. Wold,et al.  Know Your Neighbors: Three Phenotypes in Null Mutants of the Myogenic bHLH Gene MRF4 , 1996, Cell.

[63]  S. Camper,et al.  Dosage requirement of Pitx2 for development of multiple organs. , 1999, Development.

[64]  P. Scambler,et al.  Tbx1 regulation of myogenic differentiation in the limb and cranial mesoderm , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[65]  T. Braun,et al.  Comparative expression analysis of Pax3 and Pax7 during mouse myogenesis. , 2006, The International journal of developmental biology.

[66]  F. Wachtler,et al.  The extrinsic ocular muscles in birds are derived from the prechordal plate , 1984, Naturwissenschaften.

[67]  E. Olson,et al.  Control of Facial Muscle Development by MyoR and Capsulin , 2002, Science.