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Murine Creld1 controls cardiac development through activation of calcineurin/NFATc1 signaling

Elvira Mass1, Dagmar Wachten2, Anna C Aschenbrenner1

  • 1LIMES-Institute, Program Unit Development, Genetics and Molecular Physiology, Molecular Developmental Biology, University of Bonn, Carl-Troll-Strasse 31, 53115 Bonn, NRW 53115, Germany.

Developmental Cell
|April 5, 2014
PubMed

Insights

The Cysteine-Rich with EGF-Like Domains 1 (Creld1) gene regulates calcineurin/NFATc1 signaling, promoting NFATc1 dephosphorylation and nuclear translocation. Creld1 is essential for heart development and endocardial cell proliferation.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Developmental Biology

Background:

  • Calcineurin is a Ca(2+)-dependent phosphatase regulating transcription factor NFAT.
  • NFAT controls inflammatory responses and cardiac development.
  • The precise regulators of calcineurin/NFAT signaling remain incompletely understood.

Purpose of the Study:

  • To identify novel regulators of calcineurin/NFATc1 signaling.
  • To elucidate the role of the Cysteine-Rich with EGF-Like Domains 1 (Creld1) gene in this pathway.
  • To investigate Creld1's function in cardiac development.

Main Methods:

  • Biochemical assays to assess protein complex formation and phosphatase activity.
  • Cellular localization studies using Creld1.
  • Analysis of Creld1 knockout (Creld1KO) mice for cardiac phenotypes.
  • Investigation of gene expression in endocardial cells.

Main Results:

  • Creld1 directly regulates calcineurin/NFATc1 signaling by promoting NFATc1 dephosphorylation and nuclear translocation.
  • Creld1 forms a complex with calcineurin regulatory subunit CnB, influencing its activity.
  • Creld1 localization at the endoplasmic reticulum is crucial for its function.
  • Creld1 is essential for embryonic heart development and VEGF-dependent endocardial cell proliferation via NFATc1 target gene expression.

Conclusions:

  • Creld1 is a novel and essential regulator of the calcineurin/NFATc1 signaling pathway.
  • Creld1 plays a critical role in cardiac development and endocardial cell function.
  • Targeting Creld1 may offer therapeutic avenues for cardiovascular diseases.

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