title: Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy.
abstract: Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD.
authors.affiliation: Aix-Marseille Université, CNRS, IBDML UMR 7288, Parc Scientifique de Luminy, Case 907, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Caruso
authors.forename: Balàzs
authors.initials: B
authors.lastname: Herberth
authors.forename: Marc
authors.initials: M
authors.lastname: Bartoli
authors.forename: Francesca
authors.initials: F
authors.lastname: Puppo
authors.forename: Julie
authors.initials: J
authors.lastname: Dumonceaux
authors.forename: Angela
authors.initials: A
authors.lastname: Zimmermann
authors.forename: Simon
authors.initials: S
authors.lastname: Denadai
authors.forename: Marie
authors.initials: M
authors.lastname: Lebossé
authors.forename: Stephane
authors.initials: S
authors.lastname: Roche
authors.forename: Linda
authors.initials: L
authors.lastname: Geng
authors.forename: Frederique
authors.initials: F
authors.lastname: Magdinier
authors.forename: Shahram
authors.initials: S
authors.lastname: Attarian
authors.forename: Rafaelle
authors.initials: R
authors.lastname: Bernard
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
authors.forename: Nicolas
authors.initials: N
authors.lastname: Levy
authors.forename: Françoise
authors.initials: F
authors.lastname: Helmbacher
mesh_terms: D000328:Adult; D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D024510:Muscle Development / Q000235:genetics*; D009132:Muscles / Q000378:metabolism / Q000503:physiopathology*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics* / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity
chemical_list: D015820:Cadherins; C502403:FAT1 protein, human