Whole-genome Omics delineates the function of CCM1 within the CmPn networks

Abstract

IntroductionCerebral cavernous malformations (CCMs) are abnormal dilations of brain capillaries that increase the risk of hemorrhagic strokes. Mutations in the KRIT1, MGC4607, and PDCD10 genes cause CCMs, with mutations in CCM1 accounting for about 50% of familial cases. The disorder exhibits incomplete penetrance, meaning that individuals with CCM may appear normal initially, but once symptoms manifest, their brains have already suffered irreversible damage. Compromised blood-brain barrier (BBB) is crucial in regulating the flow of substances between the blood and the central nervous system, which can result in hemorrhagic CCMs. Progesterone and its derivatives have been studied for their impact on maintaining BBB integrity. CCM2 interacts with CCM1 and CCM3, forming the CCM signaling complex (CSC), which connects classic and non-classic progesterone signaling to establish the CmPn signaling network, vital in preserving BBB integrity. MethodsThe study aimed to explore the relationship between CCM1 and key pathways of the CmPn signaling network, utilizing a toolset comprising three mouse embryonic fibroblast lines (MEFs) with distinct CCM1 expression levels. Omics and systems biology analysis were performed to investigate Ccm1-mediated signaling within the CmPn signaling network. ResultsThe findings suggest that CCM1 plays a critical role in controlling cellular processes in response to different progesterone-mediated actions within CmPn/CmP signaling networks, partly by regulating gene transcription. This function is crucial for preserving the integrity of microvessels, indicating that targeting CCM1 could hold promise as a therapeutic approach for this condition.