Mechanisms of Brain Morphogenesis and Pathogenesis

A central question in developmental neuroscience is the elucidation of the genetic programs that govern mammalian brain morphogenesis. Determining the cellular and molecular basis of rare congenital brain disorders, including those that disrupt the structure of the neocortex, promises not only to inform our understanding of disease pathogenesis, but also to provide mechanistic insight into human cortical development.

Cerebral Cavernous Malformations (CCM; OMIM 116860) are common vascular anomalies of the central nervous system that can cause seizures, focal neurological deficits, or hemorrhagic stroke. Most CCMs are solitary and occur sporadically; however, multiple lesions are a hallmark of autosomal dominant disease. Sporadic lesions are characterized by remarkable genetic heterogeneity and involve somatic mutations in CCM1, CCM2, or CCM3, or, more commonly, somatic activating mutations in the oncogene PIK3CA. Individuals with familial CCM inherit a germline loss-of-function monoallelic mutation in one of three CCM genes, and are thought to acquire a second-hit, somatic mutation that is necessary for lesion formation.