| Dandy Walker malformation (DWM) is a common, heterogeneous congenital brain structural abnormality of the cerebellum that is linked to at least four loci in humans. This thesis describes the identification of FOXC1 as the major DWM-causative gene on chromosome 6p25.3 using a combination of human copy number variant (CNV) and mouse in situ hybridization expression analyses. In parallel, examination of Foxc1 mouse mutants revealed striking deficits in early cerebellar development, including an early expansion of roof plate and choroid plexus and premature loss of Math1 in cerebellar rhombic lip progenitors. Mice with a hypomorphic Foxc1 allele additionally displayed abnormalities in midline fusion, foliation, and Purkinje cell morphology consistent with a mouse DWM-like phenotype. I further determined that Foxc1 is not expressed in the developing cerebellum, rather it is expressed in the adjacent mesenchyme, which regulates secretion of trophic factors required for cerebellar development and implicates skull developmental abnormalities as an integral component of DWM pathogenesis. Additional MRI analysis indicated that mutation of the human FOXC1 gene alone is sufficient to cause cerebellar abnormalities, but not the full DWM phenotype. Thus, human FOXC1 regulates cerebellar development, but must interact with other 6p25.3 genes to cause the complete DWM phenotype.In addition to studies of DMW, the hypothesis that cerebellar malformation loci represent an important subset of autism spectrum disorder (ASD) loci was also tested. I determined that two DWM deletion 6p25.3 (FOXC1 CNV) patients were also diagnosed with ASD and that deletion 22q13 ASD patients have a previously undescribed cerebellar malformation. I also initiated analysis of ASD-associated EN2 and MET polymorphisms in our cerebellar malformation patient population. Reciprocally, I initiated association and CNV analyses of FOXC1 and other cerebellar malformation genes in an ASD patient population. These studies are ongoing, but have begun to provide support for a common genetic etiology between ASD and cerebellar malformations. Together, the studies detailed in my thesis provide novel mechanistic insight into the pathogenesis of both DWM and ASD and highlight the importance of reciprocal diagnostic evaluation for patients with these disorders identified in the clinic. |
