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.

SORBS2transcription is activated by telomere position effect–over long distance upon telomere shortening in muscle cells from patients with facioscapulohumeral dystrophy

“…However, in a number of cases, the role of DUX4 remains unclear due to the complexity of its expression pattern (Dixit et al 2007;Snider et al 2010;Tassin et al 2013), low mRNA and protein abundance Ferreboeuf et al 2014), and the presence of DUX4 in unaffected individuals (Jones et al 2012;Broucqsault et al 2013). Thus, DUX4 might not be sufficient to explain the wide variability of the pathology, the muscle specificity and asymmetry, or the age-related onset suggesting that other factors are likely involved (Cabianca et al 2012;Caruso et al 2013;Stadler et al 2013;Mariot et al 2015;Puppo et al 2015).…”

“…One hypothesis to explain how the contraction of D4Z4 leads to deregulation of nearby genes in FSHD (van Geel et al 1999;Jiang et al 2003;Celegato et al 2006;Caruso et al 2013) on 4q is via chromosomal looping and/or epigenetic modifications Gaillard et al 2014;Jones et al 2014). The number of D4Z4 repeats might influence the ability of repressor or enhancer binding sequences within the repeats to loop and form contacts with other genes in the 4q region and thereby influence transcription (Pirozhkova et al 2008;Tsumagari et al 2008;Bodega et al 2009;Ottaviani et al 2009).…”

Fat3 and Ena/VASP proteins influence the emergence of asymmetric cell morphology in the developing retina

“…Fat4 is the vertebrate ortholog of Drosophila fat and Fat1-Fat3 share greater sequence similarity with Drosophila fat-like (Tanoue and Takeichi, 2005). Whereas Fat4 plays a conserved role in planar polarity (Saburi et al, 2008), little is known about how Fat-like proteins might influence cell shape and orientation in any system (Sadeqzadeh et al, 2014), with only a handful of possible polarity phenotypes described in either flies (Viktorinova et al, 2009) or vertebrates (Caruso et al, 2013;Le Pabic et al, 2014;Saburi et al, 2012).…”

Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development

“…In addition to kidney defects, Fat1 mutants have deformed eyes and craniofacial malformations, with low incidence of holoprosencephaly, which has not been well described or characterized. Fat1 is also involved in muscle formation, and linked to facioscapulohumeral dystrophy (Caruso et al, 2013). At the cellular level, Fat1 interacts with Mena/ Vasp proteins to regulate cell migration and actin dynamics in cell culture (Moeller et al, 2004;Tanoue and Takeichi, 2004;Hou and Sibinga, 2009).…”