The role of CCM2 in embryonic development

National Institute Of Allergy And Infectious Diseases

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Abstract

The aim of the project is to understand the mechanisms by which loss of CCM proteins, and specifically of CCM2, may lead to the development of Cerebral Cavernous Malformations (CCMs) in humans. CCMs are sporadically acquired or inherited vascular anomalies of the CNS characterized by clusters of dilated thin-walled blood vessels that predispose individuals to seizures and even fatal strokes. The CCM2 gene is one of three genetic loci, along with CCM1 and CCM3, which are found mutated in patients with the inherited form of CCM. Disease is thought to be initiated upon somatic loss of the second allele opposite the functionally inactivated inherited CCM mutant allele. The CCM proteins are adaptors involved in signaling pathways that can involve the MAP3 kinase MEKK3. To better understand the physiologic role of the CCM2 adaptor, we have generated mouse models deficient in this protein. We determined that loss of CCM2 results in embryonic lethality, apparently due to an early block in angiogenesis, consistent with finding by others. In FY 2011 we have also generated and used conditionally deficient CCM2 mice to demonstrate that loss of this protein in endothelial cells specifically results in an early block in agiogenesis in mouse embryos;this strengthens the notion that Cerebral Cavernous Malformations are caused by loss of CCM proteins in endothelial cells as well. In FY 2011 we also succeeded in developing a mouse model for the human CCM disease: We conditionally ablated CIKS in adult mice and demonstrated that this led to cerebral cavernous malformations and neural and behavioral defects that very much mimicked the human disease. This mouse model provides avenues to further investigate the disease process and it provides a way to evaluate potential therapeutic strategies that may ultimately be used in human CCM patients.