Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy.

Nathalie Caruso,Rafaelle Bernard,Frederique Magdinier,Marc Bartoli,Shahram Attarian,Julie Dumonceaux,Angela Zimmermann,Simon Denadai,Marie Lebossé,Linda Geng,Françoise Helmbacher,Nicolas Levy,Francesca Puppo,Balàzs Herberth,Flavio Maina,Stephane Roche

doi:10.1371/journal.pgen.1003550

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.

Highlights

Developmental genetics has provided considerable insight into the regulatory networks controlling overall skeletal muscle development
During embryogenesis, following delamination from the dermomyotomal lip at forelimb levels, cutaneous maximus (CM) precursors, identified through their specific expression of GDNF, reach the base of the limb, turn, and spread under the skin in a radial manner [39,40] (Figure 1A). This migration pattern reflects collective and polarized cell migration, visible owing to expression of the MLC3F2E reporter line or of the muscle fate marker MyoD, through the formation of chains of myoblasts aligned in radial directions (Figure 1B and 1E top right panel)
We found that CM myoblasts express Fat1 RNA and appear to be positioned in a subcutaneous layer which itself expresses Fat1 RNA, this surrounding subcutaneous tissue displaying a rostrocaudal gradient of

Summary

Introduction

Developmental genetics has provided considerable insight into the regulatory networks controlling overall skeletal muscle development. Genes controlling diversification too are likely to be of clinical significance [2,3,4], since several human muscular dystrophies do not affect all muscles evenly, but target regionalized groups [5]. This is true for limb girdle muscular dystrophy (LGMD), oculopharyngeal muscular dystrophy (OPMD), myotonic dystrophies with oculomotor involvement, distal myopathies, scapuloperoneal dystrophy, and facioscapulohumeral dystrophy (FSHD) [5,6]. In no case is the rationale for this geographic specificity currently understood

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