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The Calcineurin Variant CnAβ1 Controls Mouse Embryonic Stem Cell Differentiation by Directing mTORC2 Membrane

Jesús M Gómez-Salinero1, Marina M López-Olañeta1, Paula Ortiz-Sánchez1

  • 1Myocardial Pathophysiology Program, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.

Cell Chemical Biology
|October 18, 2016
PubMed

Insights

Alternative splicing regulator MBNL1 promotes the calcineurin Aβ1 variant (CnAβ1) in mouse embryonic stem cells (mESCs). This impacts mTORC2 localization and signaling, crucial for mesoderm differentiation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • Embryonic stem cells (ESCs) differentiate into all body cell lineages.
  • Molecular mechanisms of ESC differentiation, particularly alternative splicing, are not fully understood.

Purpose of the Study:

  • Investigate the role of alternative splicing in mouse ESC (mESC) differentiation.
  • Elucidate the function of the MBNL1 splicing regulator and its downstream targets.

Main Methods:

  • Studied alternative splicing in mESCs using MBNL1.
  • Analyzed the calcineurin Aβ variant CnAβ1 and its interaction with Cog8.
  • Investigated mTORC2 complex localization and AKT/GSK3β/β-catenin signaling pathway activity.

Main Results:

  • MBNL1 promotes the generation of the atypical CnAβ1 variant in mESCs.
  • CnAβ1 interacts with Cog8, localizing it to the Golgi apparatus.
  • CnAβ1 regulates mTORC2 localization and impacts mesoderm specification via the AKT/GSK3β/β-catenin pathway.

Conclusions:

  • Unveiled the structural basis and mechanism of action for CnAβ1.
  • Demonstrated CnAβ1's critical role in mESC differentiation towards the mesodermal lineage.
Keywords:
AktCnAβ1Golgi apparatusRictorcalcineurinmTORsplicingstem cells

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