Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY Congenital hydrocephalus (CH) is the most common developmental malformation of the brain affecting 1/1000 births. CH has been classically attributed to failed cerebrospinal fluid (CSF) homeostasis and therefore treated by surgical CSF diversion, with high morbidity and failure rates. The persistence of post- surgical ventriculomegaly in many patients, often with poor neurodevelopmental outcomes, raises questions about our current paradigms of CH and its treatment. Significant gaps in our understanding of the molecular pathogenesis of CH impede the development of preventive measures, targeted therapies, and improved prognostication. By whole exome sequencing, the Kahle lab has identified heterozygous de novo mutations in the TRIM71/lin-41 as the most common genetic cause of human sporadic CH (Jin et al. 2020, Nature Medicine). TRIM71 encodes an RNA-binding protein first discovered in C. elegans as a heterochronic gene that regulates developmental timing of epidermal stem cells. Despite its remarkable evolutionary conservation across phylogeny and robust expression in prenatal neural stem cells (NSCs), the roles of TRIM71 in mammalian brain development and CH are essentially unknown. In preliminary work, I have shown that mouse lines with the murine homolog of the human TRIM71 CH mutation R608H (Trim71R595H/+) or with conditional NSC-specific Trim71 deletion (Nestin-Trim71fl/fl) both recapitulate the severe neonatal-onset communicating hydrocephalus of human patients harboring TRIM71 mutations. The objective of my proposal is to further characterize these models to increase knowledge of human brain development and CH pathogenesis. I hypothesize TRIM71 mutant ventriculomegaly results not from primary cerebrospinal fluid (CSF) over-accumulation, but rather from impaired neurogenesis related to reduced NSC proliferation and precocious NSC differentiation. Aim 1 will characterize the neuroanatomy and CSF physiology of TRIM71-mutant hydrocephalus using brain magnetic resonance imaging (MRI) and direct measurements of CSF hydrodynamics. Aim 2 will elucidate the cellular mechanisms of TRIM71-mutant hydrocephalus using immunofluorescent studies in Trim71 CH mutant mice complemented by in vitro assays using primary NSC cultures. The demonstration that dysregulated neurogenesis rather than primary CSF over-accumulation underlies some CH cases could have paradigm-changing implications that could lead to improved diagnostic, prognostic, and therapeutic strategies, including the prediction of which CH patients may or may not benefit from neurosurgical CSF shunting. These studies will be conducted as part of our long-term goal to develop precision medicine therapies for CH.
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