Krit1 knockout down-regulates Rap1A activity: a possible explanation for Cerebral Cavenous Malformations pathogenesis

Krit1 has been identified as the disease gene for an autosomal dominant form of Cerebral Cavernous Malformations (CCM). CCM are vascular malformations characterized by abnormally enlarged capillary cavities without intervening neural parenchyma and may cause seizures, intracerebral haemorrhage, or focal neurological deficits. To gain insights into the CCM pathogenetic mechanisms as well as into the physiological function of the Krit1 protein we generated mice lacking Krit1 gene. Mice heterozygous for the mutant allele are phenotypically normal. In contrast, homozygous mutant embryos die in mid-gestation (E9.5), demonstrating a crucial role for Krit1 during early mouse development. In addition, we used Krit1-null embryonic cells in order to test at the molecular level the effect of the absence of Krit1. In particular, we found that the activation level of the Ras-like GTPase Rap1A, a known Krit1 interactor, is down-regulated. Taken together with our recent finding that Rap1A plays a major role in the regulation of cell-cell and cell-matrix adhesion (1), this result suggests that Krit1 mutations could cause CCM pathogenesis by affecting Rap1A signalling. (1) Balzac F, Avolio M, Degani S, Kaverina I, Torti M, Silengo L, Small JV, Retta SF. E-cadherin endocytosis regulates the activity of Rap1: a traffic light GTPase at the crossroads between cadherin and integrin function. J Cell Sci. 2005 Oct 15;118(Pt 20):4765-83.