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1.
Mol Biol Cell ; 32(3): 260-273, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296226

RESUMO

Mutations in two different domains of the ubiquitously expressed TRIM32 protein give rise to two clinically separate diseases, one of which is Limb-girdle muscular dystrophy type 2H (LGMD2H). Uncovering the muscle-specific role of TRIM32 in LGMD2H pathogenesis has proven difficult, as neurogenic phenotypes, independent of LGMD2H pathology, are present in TRIM32 KO mice. We previously established a platform to study LGMD2H pathogenesis using Drosophila melanogaster as a model. Here we show that LGMD2H disease-causing mutations in the NHL domain are molecularly and structurally conserved between fly and human TRIM32. Furthermore, transgenic expression of a subset of myopathic alleles (R394H, D487N, and 520fs) induce myofibril abnormalities, altered nuclear morphology, and reduced TRIM32 protein levels, mimicking phenotypes in patients afflicted with LGMD2H. Intriguingly, we also report for the first time that the protein levels of ßPS integrin and sarcoglycan δ, both core components of costameres, are elevated in TRIM32 disease-causing alleles. Similarly, murine myoblasts overexpressing a catalytically inactive TRIM32 mutant aberrantly accumulate α- and ß-dystroglycan and α-sarcoglycan. We speculate that the stoichiometric loss of costamere components disrupts costamere complexes to promote muscle degeneration.


Assuntos
Proteínas de Drosophila/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Sarcoglicanas/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Animais Geneticamente Modificados , Costâmeros/metabolismo , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Drosophila melanogaster , Humanos , Integrinas/metabolismo , Integrinas/fisiologia , Músculo Esquelético/metabolismo , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Mutação , Miofibrilas/metabolismo , Neurogênese , Fenótipo , Sarcoglicanas/fisiologia , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/genética
2.
Genetics ; 206(1): 199-213, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28249984

RESUMO

Adult muscle precursor (AMP) cells located in the notum of the larval wing disc undergo rapid amplification and eventual fusion to generate the Drosophila melanogaster indirect flight muscles (IFMs). Here we find that loss of Moleskin (Msk) function in these wing disc-associated myoblasts reduces the overall AMP pool size, resulting in the absence of IFM formation. This myoblast loss is due to a decrease in the AMP proliferative capacity and is independent of cell death. In contrast, disruption of Msk during pupal myoblast proliferation does not alter the AMP number, suggesting that Msk is specifically required for larval AMP proliferation. It has been previously shown that Wingless (Wg) signaling maintains expression of the Vestigial (Vg) transcription factor in proliferating myoblasts. However, other factors that influence Wg-mediated myoblast proliferation are largely unknown. Here we examine the interactions between Msk and the Wg pathway in regulation of the AMP pool size. We find that a myoblast-specific reduction of Msk results in the absence of Vg expression and a complete loss of the Wg pathway readout ß-catenin/Armadillo (Arm). Moreover, msk RNA interference knockdown abolishes expression of the Wg target Ladybird (Lbe) in leg disc myoblasts. Collectively, our results provide strong evidence that Msk acts through the Wg signaling pathway to control myoblast pool size and muscle formation by regulating Arm stability or nuclear transport.


Assuntos
Proteínas do Domínio Armadillo/genética , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/biossíntese , Fatores de Transcrição/genética , Proteína Wnt1/biossíntese , Animais , Proliferação de Células/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Larva/genética , Larva/crescimento & desenvolvimento , Desenvolvimento Muscular/genética , Mioblastos/metabolismo , Proteínas Nucleares/genética , Transdução de Sinais , Asas de Animais/crescimento & desenvolvimento , Proteína Wnt1/genética
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