ZFIN ID: ZDB-PUB-130129-1
Ccm2-like is required for cardiovascular development as a novel component of the Heg-CCM pathway
Rosen, J.N., Sogah, V.M., Ye, L.Y., and Mably, J.D.
Date: 2013
Source: Developmental Biology   376(1): 74-85 (Journal)
Registered Authors: Mably, John, Rosen, Jonathan N.
Keywords: CCM, cerebral cavernous malformation, Ccm1, Ccm2, Heg, zebrafish
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cardiovascular System/embryology*
  • Cardiovascular System/metabolism
  • DNA Primers/genetics
  • Immunoblotting
  • In Situ Hybridization
  • Membrane Glycoproteins/metabolism*
  • Mice
  • Microfilament Proteins/genetics
  • Microfilament Proteins/metabolism*
  • Microscopy
  • Microtubule-Associated Proteins/genetics
  • Microtubule-Associated Proteins/metabolism*
  • Molecular Sequence Data
  • Morpholinos
  • Phenotype*
  • Proto-Oncogene Proteins/metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Signal Transduction/genetics
  • Signal Transduction/physiology*
  • Zebrafish Proteins/metabolism*
PubMed: 23328253 Full text @ Dev. Biol.

The Heart of Glass-Cerebral Cavernous Malformation (Heg-CCM) pathway is essential for normal cardiovascular development in zebrafish and mouse. In zebrafish, the Heg-CCM pathway mutants santa (ccm1/san), valentine (ccm2/vtn), and heart of glass (heg) exhibit severely dilated hearts and inflow tracts and a complete absence of blood circulation. We identified a novel gene based on its sequence identity with ccm2, which we have named ccm2-like (ccm2l), and characterized its role in cardiovascular development. Disruption of ccm2l by morpholino injection causes dilation of the atrium and inflow tract and compromised blood circulation. Morpholino co-injection experiments identify ccm2l as an enhancer of the characteristic Heg-CCM dilated heart phenotype, and we find that ccm2 overexpression can partially rescue ccm2l morphant defects. Finally, we show that Ccm2l binds Ccm1 and perform deletion and mutational analyses to define the regions of Ccm1 that mediate its binding to Ccm2l and its previously established interactors Ccm2 and Heg. These genetic and biochemical data argue that ccm2l is a necessary component of the Heg-CCM pathway.