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.

The precise control of motor neuron (MN) death and survival following initial innervation of skeletal muscle targets is a key step in sculpting a functional motor system, but how this is regulated at the level of individual motor pools remains unclear. Hepatocyte growth factor (HGF) and its receptor Met play key developmental roles in both muscle and MNs. We generated mice (termed "Nes-Met") in which met is inactivated from midembryonic stages onward in the CNS only. Adult animals showed motor behavioral defects suggestive of impaired innervation of pectoral muscles. Correspondingly, in neonatal spinal cords of Nes-Met mutants, we observed death of a discrete population of pea3-expressing MNs at brachial levels. Axonal tracing using pea3 reporter mice revealed a novel target muscle of pea3-expressing MNs: the pectoralis minor muscle. In Nes-Met mice, the pectoralis minor pool initially innervated its target muscle, but required HGF/Met for survival, hence for proper maintenance of muscle innervation. In contrast, HGF/Met was dispensable for the survival of neighboring Met-expressing MN pools, despite its earlier functions for their specification and axon growth. Our results demonstrate the exquisite degree to which outcomes of signaling by receptor tyrosine kinases are regulated on a cell-by-cell basis. They also provide a model for one way in which the multiplicity of neurotrophic factors may allow for regulation of MN numbers in a pool-specific manner.

We propose a revised model for FSHD in which FAT1 levels might play a role in determining which muscles will exhibit early and late disease onset, whereas DUX4 may worsen the muscle phenotype.