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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
Published on: June 3, 2016
Modulation of Rho GTPase signaling regulates a switch between adipogenesis and myogenesis
Raffaella Sordella1, Wei Jiang, Guang-Chao Chen
1Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA.
Abstract:
Mature adipocytes and myocytes are derived from a common mesenchymal precursor. While IGF-1 promotes the differentiation of both cell types, the signaling pathways that specify the distinct cell fates are largely unknown. Here, we show that the Rho GTPase and its regulator, p190-B RhoGAP, are components of a critical switch in the adipogenesis-myogenesis "decision." Cells derived from embryos lacking p190-B RhoGAP exhibit excessive Rho activity, are defective for adipogenesis, but undergo myogenesis in response to IGF-1 exposure. In vitro, activation of Rho-kinase by Rho inhibits adipogenesis and is required for myogenesis. The activation state of Rho following IGF-1 signaling is determined by the tyrosine-phosphorylation status of p190-B RhoGAP and its resulting subcellular relocalization. Moreover, adjusting Rho activity is sufficient to alter the differentiation program of adipocyte and myocyte precursors. Together, these results identify the Rho GTPase as an essential modulator of IGF-1 signals that direct the adipogenesis-myogenesis cell fate decision.
Insights
The Rho GTPase acts as a key switch in cell differentiation. It controls whether precursor cells become fat cells (adipogenesis) or muscle cells (myogenesis) following IGF-1 signaling.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Signaling
Background:
- Mature adipocytes and myocytes originate from a shared mesenchymal precursor.
- Insulin-like Growth Factor 1 (IGF-1) influences both adipogenesis and myogenesis, but specific downstream pathways remain unclear.
Purpose of the Study:
- To elucidate the signaling pathways governing the adipogenesis-myogenesis cell fate decision.
- To identify key molecular regulators involved in IGF-1-mediated differentiation.
Main Methods:
- Investigated the role of Rho GTPase and its regulator p190-B RhoGAP in cell differentiation.
- Utilized knockout embryos lacking p190-B RhoGAP to assess cellular responses.
- Performed in vitro experiments to study Rho-kinase activation and its effects on adipogenesis and myogenesis.
Main Results:
- Absence of p190-B RhoGAP leads to elevated Rho activity, impaired adipogenesis, and promoted myogenesis upon IGF-1 stimulation.
- Rho-kinase activation by Rho inhibits adipogenesis and is essential for myogenesis.
- IGF-1 signaling modulates Rho activity via tyrosine phosphorylation and subcellular localization of p190-B RhoGAP.
Conclusions:
- The Rho GTPase functions as a critical switch in the adipogenesis-myogenesis cell fate decision.
- p190-B RhoGAP acts as a molecular regulator determining Rho activity and directing cell differentiation pathways.
- Modulating Rho activity is sufficient to redirect precursor cell differentiation programs.
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