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Shisa2 regulates the fusion of muscle progenitors.

ABSTRACT: Adult skeletal muscles are comprised of multinuclear muscle cells called myofibers. During skeletal muscle development and regeneration, mononuclear progenitor cells (myoblasts) fuse to form multinuclear myotubes, which mature and become myofibers. The molecular events mediating myoblast fusion are not fully understood. Here we report that Shisa2, an endoplasmic reticulum (ER) localized protein, regulates the fusion of muscle satellite cell-derived primary myoblasts. Shisa2 expression is repressed by Notch signaling, elevated in activated compared to quiescent satellite cells, and further upregulated during myogenic differentiation. Knockdown of Shisa2 inhibits the fusion of myoblasts without affecting proliferation. Conversely, Shisa2 overexpression in proliferating myoblasts inhibits their proliferation but promotes premature fusion. Interestingly, Shisa2-overexpressing nascent myotubes actively recruit myoblasts to fuse with. At the molecular level, Rac1/Cdc42-mediated cytoskeletal F-actin remodeling is required for Shisa2 to promote myoblast fusion. These results provide a novel mechanism through which an ER protein regulates myogenesis.

SUBMITTER: Liu Z

PROVIDER: S-EPMC6171505 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Shisa2 regulates the fusion of muscle progenitors.

Liu Zuojun Z Wang Chao C Liu Xiaoqi X Kuang Shihuan S

Stem cell research 20180706

Adult skeletal muscles are comprised of multinuclear muscle cells called myofibers. During skeletal muscle development and regeneration, mononuclear progenitor cells (myoblasts) fuse to form multinuclear myotubes, which mature and become myofibers. The molecular events mediating myoblast fusion are not fully understood. Here we report that Shisa2, an endoplasmic reticulum (ER) localized protein, regulates the fusion of muscle satellite cell-derived primary myoblasts. Shisa2 expression is repress ...[more]

PMID: 30007221

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Project description:In skeletal muscle differentiation, muscle-specific genes are regulated by two groups of transcription factors, the MyoD and MEF2 families, which work together to drive the differentiation process. Here we show that ERK5 regulates muscle cell fusion through Klf transcription factors. The inhibition of ERK5 activity suppresses muscle cell fusion with minimal effects on the expression of MyoD, MEF2, and their target genes. Promoter analysis coupled to microarray assay reveals that Klf-binding motifs are highly enriched in the promoter regions of ERK5-dependent upregulated genes. Remarkably, Klf2 and Klf4 expression are also upregulated during differentiation in an ERK5-dependent manner, and knockdown of Klf2 or Klf4 specifically suppresses muscle cell fusion. Moreover, we show that the Sp1 transcription factor links ERK5 to Klf2/4, and that nephronectin, a Klf transcriptional target, is involved in muscle cell fusion. Therefore, an ERK5/Sp1/Klf module plays a key role in the fusion process during skeletal muscle differentiation. To identify those genes whose expression levels are regulated by the ERK5 pathway in differentiating C2C12 cells, we performed genome-wide analysis by using Affymetrix GeneChip oligonucleotide microarrays. We performed two independent experiments. For each experiment, we used five samples: cells in growth medium (0 day), lacZ-infected cells at two time points (2.5 days and 4.5 days of differentiation) and dnMEK5-infected cells at two time points (2.5 days and 4.5 days of differentiation). Each virus was infected at 1 day of differentiation. Total RNA was prepared using the RNeasy Mini Kit (Qiagen) according to the manufacturer’s instructions. The total RNA of each condition was obtained from two independent experiments. Synthesis of cDNA in vitro transcription and biotin labeling cRNA, and hybridization to the Mouse Genome 430 2.0 array (Affymetrix) were performed according to Affymetrix protocols. Hybridized arrays were scanned using an Affymetrix GeneChip Scanner. Scanned Chip images were analyzed with GeneChip operating Software v.1.4 (GCOS) and GeneSpring GX 11.0.2. (Agilent technologies).

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Shisa2 regulates the fusion of muscle progenitors.

Publications

Shisa2 regulates the fusion of muscle progenitors.

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