Analysis of Congenital Hydrocephalus Genes in Xenopus

Project Summary Congenital Hydrocephalus (CH), the pathological expansion of the cerebral ventricles due to cerebrospinal fluid (CSF) accumulation, is a common birth defect affecting 1 in every 1000 births, with high mortality and morbidity. Treatment options are limited to surgery, which has a 50% failure rate. The lack of treatment modalities is, in part, due to our incomplete understanding of hydrocephalus pathogenesis. Current human genetics studies identified novel candidate genes (SMARCC1, TRIM71, PTCH1, SHH) in patients with CH. Despite their known roles in neural stem cells, their role in hydrocephalus pathogenesis is unknown. In this work, we will use the frog Xenopus model system to understand the underlying pathogenesis. Our recent work paired optical coherence tomography imaging (OCT) and CRISPR/CAS9 system with the frog Xenopus to model human congenital hydrocephalus. We demonstrated that OCT imaging of mutant tadpoles could readily detect hallmarks of human hydrocephalus, including aqueductal stenosis and ventriculomegaly. Importantly Xenopus, as a model system, can rapidly evaluate CH candidate genes and distinguish communicating vs. non-communicating pathogenesis mechanisms. Our central hypothesis is that the pathogenesis of CH due to different genetic backgrounds will be discretely different for ventricular morphology, CSF flow network, and neural progenitor cell fate, which can have important implications for treatment. Overall, our goal is to shed light on the mechanism of hydrocephalus pathogenesis to identify novel targets for medical management options.