Dystrophin glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation. Morikawa Y et al. (2017) The regenerative capacity of the adult mammalian heart is limited because of the reduced ability of cardiomyocytes (CMs) to progress through mitosis(1). The regenerative capacity of endogenous CMs exists at birth but is lost postnatally, with subsequent organ growth occurring through CM hypertrophy(2,3). The Hippo pathway, a conserved kinase cascade, inhibits CM proliferation in the developing heart to control heart size and in the adult heart to prevent regeneration(4,5). The dystrophin glycoprotein complex (DGC), a multicomponent transmembrane complex linking the actin cytoskeleton to extracellular matrix, is essential for CM homeostasis. DGC deficiency in humans results in muscular dystrophy, including lethal Duchenne muscular dystrophy (DMD). We found that the DGC component dystroglycan 1 (DAG1) directly binds to Hippo pathway effector Yap to inhibit CM proliferation. The Yap-DAG1 interaction was enhanced by Hippo-induced Yap phosphorylation, revealing a connection between Hippo pathway function and the DGC. After injury, Hippo-deficient postnatal hearts maintained organ size control by repairing the defect with correct dimensions, whereas postnatal hearts doubly deficient for Hippo and the DGC showed CM overproliferation at the injury site. In mature Mdx mouse hearts-a model of DMD-Hippo deficiency protected against overload-induced heart failure.//////////////////
NCBI Summary:
The zeta-sarcoglycan gene measures over 465 kb and localizes to 8p22. This protein is part of the sarcoglycan complex, a group of 6 proteins. The sarcoglycans are all N-glycosylated transmembrane proteins with a short intra-cellular domain, a single transmembrane region and a large extra-cellular domain containing a carboxyl-terminal cluster with several conserved cysteine residues. The sarcoglycan complex is part of the dystrophin-associated glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extra-cellular matrix. [provided by RefSeq, Jul 2008]
General function
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Cellular localization
Extracellular Matrix
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Ovarian function
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Expression regulated by
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Ovarian localization
Granulosa
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Transactivation of microRNA-383 by Steroidogenic Factor-1 Promotes Estradiol Release from Mouse Ovarian Granulosa Cells by Targeting RBMS1. Yin M et al. Our previous studies have shown that microRNA-383 (miR-383) is one of the most down-regulated miRNA in TGF-1-treated mouse ovarian granulosa cells (GC). However, the roles and mechanisms of miR-383 in GC function during follicular development remain unknown. In this study, we found that miR-383 was mainly expressed in GC and oocytes of mouse ovarian follicles. Overexpression of miR-383 enhanced estradiol release from GC through targeting RNA binding motif, single stranded interacting protein 1 (RBMS1). miR-383 inhibited RBMS1 by affecting its mRNA stability, which subsequently suppressed the level of c-Myc (a downstream target of RBMS1). Forced expression of RBMS1 or c-Myc attenuated miR-383-mediated steroidogenesis-promoting effects. Knockdown of the transcription factor steroidogenic factor-1 (SF-1) significantly suppressed the expression of Sarcoglycan zeta (SGCZ) (miR-383 host gene), primary and mature miR-383 in GC, indicating that miR-383 was transcriptionally regulated by SF-1. Luciferase and chromatin immunoprecipitation assays revealed that SF-1 specifically bound to the promoter region of SGCZ and directly transactivated miR-383 in parallel with SGCZ. In addition, SF-1 was involved in regulation of miR-383- and RBMS1/c-Myc-mediated estradiol release from GC. These results suggest that miR-383 functions to promote steroidogenesis by targeting RBMS1, at least in part, through inactivation of c-Myc. SF-1 acts as a positive regulator of miR-383 processing and function in GC. Understanding of regulation of miRNA biogenesis and function in estrogen production will potentiate the usefulness of miRNA in the control of reproduction and treatment of some steroid-related disorders.