title: Genesis of muscle fiber-type diversity during mouse embryogenesis relies on Six1 and Six4 gene expression.
abstract: Adult skeletal muscles in vertebrates are composed of different types of myofibers endowed with distinct metabolic and contraction speed properties. Genesis of this fiber-type heterogeneity during development remains poorly known, at least in mammals. Six1 and Six4 homeoproteins of the Six/sine oculis family are expressed throughout muscle development in mice, and Six1 protein is enriched in the nuclei of adult fast-twitch myofibers. Furthermore, Six1/Six4 proteins are known to control the early activation of fast-type muscle genes in myocytes present in the mouse somitic myotome. Using double Six1:Six4 mutants (SixdKO) to dissect in vivo the genesis of muscle fiber-type heterogeneity, we analyzed here the phenotype of the dorsal/epaxial muscles remaining in SixdKO. We show by electron microscopy analysis that the absence of these homeoproteins precludes normal sarcomeric organization of the myofiber leading to a dystrophic aspect, and by immunohistochemistry experiments a deficiency in synaptogenesis. Affymetrix transcriptome analysis of the muscles remaining in E18.5 SixdKO identifies a major role for these homeoproteins in the control of genes that are specifically activated in the adult fast/glycolytic myofibers, particularly those controlling Ca(2+) homeostasis. Absence of Six1 and Six4 leads to the development of dorsal myofibers lacking expression of fast-type muscle genes, and mainly expressing a slow-type muscle program. The absence of restriction of the slow-type program during the fetal period in SixdKO back muscles is associated with a decreased HDAC4 protein level, and subcellular relocalization of the transcription repressor Sox6. Six genes thus behave as essential global regulators of muscle gene expression, as well as a central switch to drive the skeletal muscle fast phenotype during fetal development.
authors: Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8104), Paris, France.
authors: Anne-Françoise
authors: AF
authors: Richard
authors: Josiane
authors: J
authors: Demignon
authors: Iori
authors: I
authors: Sakakibara
authors: Julien
authors: J
authors: Pujol
authors: Maryline
authors: M
authors: Favier
authors: Laure
authors: L
authors: Strochlic
authors: Fabien
authors: F
authors: Le Grand
authors: Nicolas
authors: N
authors: Sgarioto
authors: Anthony
authors: A
authors: Guernec
authors: Alain
authors: A
authors: Schmitt
authors: Nicolas
authors: N
authors: Cagnard
authors: Ruijin
authors: R
authors: Huang
authors: Claire
authors: C
authors: Legay
authors: Isabelle
authors: I
authors: Guillet-Deniau
authors: Pascal
authors: P
authors: Maire
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D024510:Muscle Development / Q000235:genetics; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000648:ultrastructure; D018485:Muscle Fibers, Skeletal / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism / Q000648:ultrastructure; D009210:Myofibrils / Q000378:metabolism / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; C490947:Six1 protein, mouse; C434485:Six4 protein, Drosophila; D014157:Transcription Factors