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The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression.

Developmental cell | Jan 26, 2015

The cerebral cavernous malformation (CCM) pathway is required in endothelial cells for normal cardiovascular development and to prevent postnatal vascular malformations, but its molecular effectors are not well defined. Here we show that loss of CCM signaling in endocardial cells results in mid-gestation heart failure associated with premature degradation of cardiac jelly. CCM deficiency dramatically alters endocardial and endothelial gene expression, including increased expression of the Klf2 and Klf4 transcription factors and the Adamts4 and Adamts5 proteases that degrade cardiac jelly. These changes in gene expression result from increased activity of MEKK3, a mitogen-activated protein kinase that binds CCM2 in endothelial cells. MEKK3 is both necessary and sufficient for expression of these genes, and partial loss of MEKK3 rescues cardiac defects in CCM-deficient embryos. These findings reveal a molecular mechanism by which CCM signaling controls endothelial gene expression during cardiovascular development that may also underlie CCM formation.

Pubmed ID: 25625206 RIS Download

Mesh terms: Animals | Carrier Proteins | Endocardium | Endothelial Cells | Kruppel-Like Transcription Factors | MAP Kinase Kinase Kinase 3 | MAP Kinase Signaling System | Mice | Mice, Transgenic | Microtubule-Associated Proteins | Mitogen-Activated Protein Kinases

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Associated grants

  • Agency: Medical Research Council, Id: MC_UU_12016/10
  • Agency: NHLBI NIH HHS, Id: R01HL102138
  • Agency: NINDS NIH HHS, Id: P01 NS092521
  • Agency: NIH HHS, Id: S10 OD016270
  • Agency: NHLBI NIH HHS, Id: T32 HL007954
  • Agency: NHLBI NIH HHS, Id: R01 HL102138
  • Agency: NIGMS NIH HHS, Id: R01 GM110174
  • Agency: NHLBI NIH HHS, Id: R01HL094326
  • Agency: NHLBI NIH HHS, Id: T32 HL007971
  • Agency: NINDS NIH HHS, Id: R01 NS075168
  • Agency: NHLBI NIH HHS, Id: T32HL007971
  • Agency: NINDS NIH HHS, Id: R01 NS080893
  • Agency: NHLBI NIH HHS, Id: R01 HL094326
  • Agency: NINDS NIH HHS, Id: R01NS075168

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