Clinical issue
Cerebral cavernous malformations (CCM) are vascular malformations that are characterized by abnormally enlarged capillary vessels and are mainly found in the central nervous system. Sporadic and familial CCM occurs in 0.1-0.5% of the population. Although the average age of diagnosis is 30, CCMs are a major cause of childhood stroke and patients present with a variety of debilitating clinical symptoms, including focal seizures, cerebral hemorrhage, focal neurological deficits and headache.
Three gene loci are linked to familial CCM: KRIT1, CCM2 and PDCD10. Similar vascular phenotypes and embryonic lethality are seen in KRIT1-, CCM2- and PDCD10-deficient animal models, which strongly suggests that these proteins are involved in a conserved signaling pathway regulating blood vessel development and integrity. Previous studies have demonstrated that KRIT1 stabilizes cell-cell contacts in the endothelium, the layer of cells that line the interior surface of blood vessels. Endothelial cell-cell contacts are defective in CCM lesions, but the molecular function of KRIT1 and its effect on CCM lesions is incompletely understood, thus hampering the development of therapeutics for this disease.
Results
The authors define a new function for KRIT1 as a negative regulator of β-catenin-driven transcription. Cytoplasmic β-catenin serves as an anchor for the cytoskeleton and participates in Wnt signaling, regulating growth and adhesion. In the nucleus, β-catenin influences gene expression. Loss of KRIT1 disrupts endothelial cell-cell (adherens) junctions, which causes the mislocalization of β-catenin away from intercellular adherens junctions and into the nucleus. β-Catenin-dependent target genes are activated, many of which, such as Vegfa, are important in vascular development. The KRIT1 protein is widely expressed and its depletion increases β-catenin signaling in multiple cell types, including epithelial cells. With this in mind, the effect of loss of KRIT1 expression on β-catenin-driven cancers was investigated in the ApcMin/+ mouse model of colon cancer, showing that KRIT1 depletion causes enhanced β-catenin-driven adenoma formation.
Implications and future directions
These studies show that loss of KRIT1 alters gene expression in endothelial cells, providing mechanistic insight into how the CCM signaling complex can affect vascular development. The data also suggest that the CCM signaling complex can regulate junctional integrity and β-catenin signaling in epithelial cells and may, therefore, modulate β-catenin-driven pathologies such as intestinal adenomatous polyps.