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WNT/?-catenin signaling plays a crucial role in myoblast fusion through regulation of nephrin expression during development.

ABSTRACT: Skeletal muscle development is controlled by a series of multiple orchestrated regulatory pathways. WNT/?-catenin is one of the most important pathways for myogenesis; however, it remains unclear how this signaling pathway regulates myogenesis in a temporal- and spatial-specific manner. Here, we show that WNT/?-catenin signaling is crucial for myoblast fusion through regulation of the nephrin (Nphs1) gene in the Myog-Cre-expressing myoblast population. Mice deficient for the ?-catenin gene in Myog-Cre-expressing myoblasts (Ctnnb1^F/F;Myog-Cre mice) displayed myoblast fusion defects, but not migration or cell proliferation defects. The promoter region of Nphs1 contains the conserved ?-catenin-binding element, and Nphs1 expression was induced by the activation of WNT/?-catenin signaling. The induction of Nphs1 in cultured myoblasts from Ctnnb1^F/F;Myog-Cre mice restored the myoblast fusion defect, indicating that nephrin is functionally relevant in WNT/?-catenin-dependent myoblast fusion. Taken together, our results indicate that WNT/?-catenin signaling is crucial for myoblast fusion through the regulation of the Nphs1 gene.

SUBMITTER: Suzuki A

PROVIDER: S-EPMC6288386 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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WNT/β-catenin signaling plays a crucial role in myoblast fusion through regulation of nephrin expression during development.

Suzuki Akiko A Minamide Ryohei R Iwata Junichi J

Development (Cambridge, England) 20181127 23

Skeletal muscle development is controlled by a series of multiple orchestrated regulatory pathways. WNT/β-catenin is one of the most important pathways for myogenesis; however, it remains unclear how this signaling pathway regulates myogenesis in a temporal- and spatial-specific manner. Here, we show that WNT/β-catenin signaling is crucial for myoblast fusion through regulation of the nephrin (<i>Nphs1</i>) gene in the <i>Myog-Cre</i>-expressing myoblast population. Mice deficient for the β-cate ...[more]

PMID: 30389854

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Project description:Testicular Sertoli cells (Sc) are main somatic component of seminiferous tubules that govern the differentiation of germ cells (Gc) and provide them physical support. Sc are the target of follicle stimulating hormone (FSH) and testosterone (T) which are known to regulate spermatogenesis. FSH and T levels in human and sub-human male primates remain high during infancy (4-6 months post birth), similar to those during puberty. Subsequently, juvenile phase is marked with low levels of these hormones. In spite of prolonged hormonal exposure, spermatogenesis is not discerned during infancy unlike that during puberty. Situation during infancy is similar to certain idiopathic male infertility, where prolonged hormone supplementation fails to initiate spermatogenesis. In our quest to determine non hormonal causes of idiopathic infertility which may reside within the Sc, we investigated the association between spermatogenesis and Sc specific gene(s) expressed differentially during puberty and infancy. Although products of several genes may be necessary for quantitatively normal spermatogenesis, one needs to investigate their roles one by one. Differential display and real time PCR analysis revealed higher expression of a known tumor suppressor, Dickkopf homolog 3 (DKK3), by pubertal monkey Sc as compared to infant Sc. To evaluate role of DKK3 in spermatogenesis, we generated DKK3 knock down mice (DKDM) using shRNA construct targeted to DKK3. In testis of adult DKDM, expression of DKK3 mRNA and protein were significantly (p<0.05) low and was associated with elevated WNT-4/?-CATENIN activity. Elevated ?-CATENIN activity is known to restrict Sc maturation. Abundant expression of infant Sc marker, Mullerian inhibiting substance (MIS), in the testes of adult DKDM confirmed lack of Sc maturation in DKDM. Gc differentiation and fertility was severely compromised in DKDM. This is the first report of role of DKK3 in the testis and DKK3 mediated regulation of spermatogenesis via WNT-4/?-CATENIN modulation.

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WNT/?-catenin signaling plays a crucial role in myoblast fusion through regulation of nephrin expression during development.

Publications

WNT/β-catenin signaling plays a crucial role in myoblast fusion through regulation of nephrin expression during development.

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