Correlation between low <scp>FAT</scp>1 expression and early affected muscle in facioscapulohumeral muscular dystrophy

Mariot, Virginie; Roche, Stéphane; Hourdé, Christophe; Portilho, Débora M.; Sacconi, Sabrina; Puppo, Francesca; Duguez, Stéphanie; Rameau, Philippe; Caruso, Nathalie; Delezoide, Anne‐Lise; Desnuelle, Claude; Bessières, Bettina; Collardeau, Sophie; Féasson, Léonard; Maisonobe, Thierry; Magdinier, Frédérique; Helmbacher, Françoise; Butler-Browne, Gillian; Mouly, Vincent; Dumonceaux, Julie

doi:10.1002/ana.24446

Cited by 34 publications

(46 citation statements)

References 41 publications

(154 reference statements)

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“…Although exogenous DUX4 can downregulate FAT1 expression when exogenously expressed in human myoblasts, shRNA-mediated DUX4 silencing in FSHD1 myoblasts did not restore FAT1 expression levels [119]. Thus, FAT1 deregulation by a pathogenic 4q35 context is not attributable to DUX4 in FSHD1 myoblasts, and might be caused by DUX4-independent mechanisms.…”

Section: Relevance For Fshdmentioning

confidence: 87%

“…This possibility was supported by the identification of pathogenic FAT1 variants in human patients, in which FSHD-like symptoms were not caused by the traditional genetic causes of FSHD [14,118]. Furthermore, FAT1 is located in the vicinity of the FSHD-associated D4Z4 array on 4q35, and its expression is downregulated in fetal and adult muscles of FSHD1 and FSHD2 patients [14,119], suggesting that traditional FSHD-causing contexts may not only enhance DUX4 expression but also lead to lowered FAT1 expression in affected muscles.…”

Section: Relevance For Fshdmentioning

confidence: 97%

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Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Helmbacher

2017

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Muscle morphogenesis is tightly coupled with that of motor neurons (MNs). Both MNs and muscle progenitors simultaneously explore the surrounding tissues while exchanging reciprocal signals to tune their behaviors. We previously identified the Fat1 cadherin as a regulator of muscle morphogenesis, and showed that it is required in the myogenic lineage to control the polarity of progenitor migration. To expand our knowledge on how Fat1 exerts its tissue-morphogenesis regulator activity, we dissected its functions by tissuespecific genetic ablation. An emblematic example of muscle under such morphogenetic control is the cutaneous maximus (CM) muscle, a flat subcutaneous muscle in which progenitor migration is physically separated from the process of myogenic differentiation, but tightly associated with elongating axons of its partner motor neurons. Here, we show that constitutive Fat1 disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool.Fat1 is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets including the CM-innervating pool. We identify mesenchyme-derived connective tissue as a cell type in which Fat1 activity is required for the non-cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel, Fat1 is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate how Fat1 coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types. Author summaryBuilding neuromuscular circuits involves a tight control of morphogenetic and regulatory events driving muscle and motor neuron development. Alterations of these processes can lead to congenital abnormalities or be at the root of human pathologies. Here, we show that the mouse Fat1 cadherin gene, a developmental regulator of muscle morphogenesis, coordinates the coupling between muscle and neuronal development by playing complementary functions in mesenchyme, muscles and motor neurons. These findings may be particularly relevant for Facioscapulohumeral dystrophy (FSHD), a muscle disease affecting subgroups of muscles in the face and shoulder, which is thought to involve developmental alterations. Although FSHD is known to traditionally result from a complex combination of genetic defects, the link between the altered molecular mechanisms and the specific set of muscles affected in patients is still poorly understood. Fat1 deficiency in mice causes phenotypes reminiscent of FSHD symptoms. Furthermore, pathogenic FAT1 variants have been identified in patients with FSHD-like phenotypes, and FAT1 expression is deregulated in classical forms of FSHD. Thus, a better understanding of the developmental functions of Fat1 could guide research on FSHD pathogenesis. In particular, by showing that Fat1 disru...

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Section: Relevance For Fshdmentioning

confidence: 87%

Section: Relevance For Fshdmentioning

confidence: 97%

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Helmbacher

2017

Preprint

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“…Furthermore, it was also recently shown that SORBS2 (ArgBP2) and SORBS1 (CAP/ponsin) also interact with the FAT1 cytoplasmic tail providing independent evidence that these are bona fide protein–protein interactions. Moreover, it is notable that SORBS2 is suspected to be pathogenic factor in facioscapulohumeral muscular dystrophy , a disease also associated with compromised FAT1 expression in muscle cells . Of the remaining binding partners identified, only immunoglobulin lambda and TRAF4 remain to be investigated in detail, but given the stringent nature of our screen we anticipate this work to yield interesting results.…”

Section: Discussionmentioning

confidence: 95%

Protein interaction screening identifies SH3RF1 as a new regulator of FAT1 protein levels

et al. 2017

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Mutations and ectopic FAT1 cadherin expression are implicated in a broad spectrum of diseases ranging from developmental disorders to cancer. The regulation of FAT1 and its downstream signalling pathways remain incompletely understood. We hypothesized that identification of additional proteins interacting with the FAT1 cytoplasmic tail would further delineate its regulation and function. A yeast two-hybrid library screen carried out against the juxtamembrane region of the cytoplasmic tail of FAT1 identified the E3 ubiquitin-protein ligase SH3RF1 as the most frequently recovered protein-binding partner. Ablating SH3RF1 using siRNA increased cellular FAT1 protein levels and stabilized expression at the cell surface, while overexpression of SH3RF1 reduced FAT1 levels. We conclude that SH3RF1 acts as a negative post-translational regulator of FAT1 levels.

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Section: Introductionmentioning

confidence: 99%

“…Several have been validated as experimental models for Duchenne muscular dystrophy (DMD) [5–8], limb girdle muscular dystrophy type 2B (LGMD-2B) [9], facioscapulohumeral muscular dystrophy (FSHD)—including mosaic-origin control lines from the same patient [10–12], and excitation-contraction coupling and calcium homeostasis [13]. These cell lines have contributed to the development of therapeutic approaches such as oligonucleotide-mediated exon skipping [5], read-through of non-sense mutations [6], and gene correction [7, 8] for DMD, to the study of ryanodine receptor 1 (RyR1) deficiency in congenital myopathies [14], cell senescence in myotonic dystrophy type I [15], the involvement of IL-6 and Akt in the pathogenesis of myasthenia gravis [16], the dysregulation of DUX4c [11] and the role of FAT1 [12] in FSHD, and the shutdown of quiescence pathways in ageing [17]. They have also been used to explore fundamental aspects of muscle cell physiology including: the role of β-arrestins in myogenesis [18], the role of MMP-14 in human myoblast collagen invasion [19], nuclear protein spreading between nearby myonuclei [20], the effects of oxidative stress on myoblast calcium-dependent proteolysis [21] and the proteome [22], engineering of 3D micro-muscles [23], and the function of miRNAs during myoblast differentiation [24], this list being non-exhaustive.…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle characteristics are preserved in hTERT/cdk4 human myogenic cell lines

et al. 2016

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BackgroundhTERT/cdk4 immortalized myogenic human cell lines represent an important tool for skeletal muscle research, being used as therapeutically pertinent models of various neuromuscular disorders and in numerous fundamental studies of muscle cell function. However, the cell cycle is linked to other cellular processes such as integrin regulation, the PI3K/Akt pathway, and microtubule stability, raising the question as to whether genetic modification related to the cell cycle results in secondary effects that could undermine the validity of these cell models.ResultsHere we subjected five healthy and disease muscle cell isolates to transcriptomic analysis, comparing immortalized lines with their parent primary populations in both differentiated and undifferentiated states, and testing their myogenic character by comparison with non-myogenic (CD56-negative) cells. Principal component analysis of global gene expression showed tight clustering of immortalized myoblasts to their parent primary populations, with clean separation from the non-myogenic reference. Comparison was made to publicly available transcriptomic data from studies of muscle human pathology, cell, and animal models, including to derive a consensus set of genes previously shown to have altered regulation during myoblast differentiation. Hierarchical clustering of samples based on gene expression of this consensus set showed that immortalized lines retained the myogenic expression patterns of their parent primary populations. Of 2784 canonical pathways and gene ontology terms tested by gene set enrichment analysis, none were significantly enriched in immortalized compared to primary cell populations. We observed, at the whole transcriptome level, a strong signature of cell cycle shutdown associated with senescence in one primary myoblast population, whereas its immortalized clone was protected.ConclusionsImmortalization had no observed effect on the myogenic cascade or on any other cellular processes, and it was protective against the systems level effects of senescence that are observed at higher division counts of primary cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13395-016-0115-5) contains supplementary material, which is available to authorized users.

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Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy

Abstract: 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.

Cited by 34 publications

References 41 publications

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

Protein interaction screening identifies SH3RF1 as a new regulator of FAT1 protein levels

Skeletal muscle characteristics are preserved in hTERT/cdk4 human myogenic cell lines

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