Agenesis of the corpus callosum (CC), the large white matter tract connecting the cerebral hemispheres,occurs in about 1:4000 individuals and in 3-5% of patients with a developmental brain disorder, in particularintellectual disability or autism spectrum disorder (ASD). CC agenesis is also present in approximately 10% ofindividuals with CHARGE syndrome, a multiple anomaly developmental disorder caused by heterozygousmutations in CHD7, which encodes a chromodomain helicase protein. Importantly, because defects in CCdevelopment can only be ascertained by post-mortem analysis or structural MRI, which is not medicallyindicated in CHARGE syndrome, they may be significantly under-diagnosed. The contribution of CC agenesisto the intellectual deficits and autistic behaviors characteristic of CHARGE syndrome remains unexplored. Inpreliminary studies, I identified a novel, highly-penetrant CC agenesis phenotype in a model of CHARGEsyndrome, wherein presumptive callosal axons failed to cross the midline, formed aberrant Probst bundles andwere misrouted to the septum. Subsequent conditional deletion of Chd7 suggested that CC agenesisdeveloped non-cell autonomously, likely involving Chd7 haploinsufficiency in a novel cell population via anunexplored mechanism. In additional fate-mapping studies, I identified the choroid plexus and the pia mater astwo potential tissues that can contribute to CC agenesis in the CHARGE model. Interestingly, emerging workhas suggested the meninges, specifically the pia, to be a critical controller of midline and callosal developmentthrough signaling and physical contact with neurons. However, the contribution of pial development to the CCagenesis and additional axon tract defects in CHARGE syndrome has never been explored. My centralhypothesis is that agenesis of the corpus callosum in CHARGE syndrome is the result of non-cell autonomousdeficits in the development or function of the midline pia mater. In this proposal, I will test this hypothesis by (1)systematic analysis of the forebrain midline populations necessary for callosum development in the animalmodel of CHARGE syndrome. Leveraging available mouse lines, I will (2) generate additional conditionaldeletions of Chd7 to dissect the potential contribution of meningeal and choroid plexus tissue to the CCphenotype. And (3) I will analyze changes in the transcriptomes of pia mater and choroid plexus cells duringcallosal development to identify downstream genes that may underpin this phenotype. Together, this work isexpected to lead to a mechanistic understanding of an underexplored phenotype that may contribute to keyaspects of the CHARGE syndrome phenotype. This line of scientific pursuit is perfectly aligned with myultimate career goal to establish an independent research program to seek a functional and translationalunderstanding of the genetic mechanisms underlying developmental brain disorders. As detailed in the trainingplan, the proposed work will integrate scientific, technical, and clinical training, as well as career developmentopportunities, that will propel me towards a career as a clinician-scientist with active research.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
