The role of CCM2 in embryonic development

National Institute Of Allergy And Infectious Diseases

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Abstract

We aim 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 often 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 initiated by the MAP3 kinase MEKK3. As a first approach to understanding the physiologic role of the CCM2 adaptor, we have generated mouse models deficient in this protein. Loss of CCM2 results in embryonic lethality, apparently due to an early block in angiogenesis, consistent with finding by others. In FY 2009 we have determined that embryonic lethality correlates not only with an apparent block in angiogenesis but also with anomalies in heart development which could constitute a primary defect. In FY 2009 we have also generated conditional knockout mice for CCM2 and with the help of these mutant mice we have determined that the early developmental defect is due to loss of CCM2 in endothelial cells and not other cell types. We are developing approaches to delete CCM2 in adult mice in hopes of generating a mouse model for the human disease. Such a model would provide avenues to investigate the disease process and it may allow for the evaluation of potential therapeutic strategies.