Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Interdepartmental Neuroscience Program

First Advisor

Kahle, Kristopher

Abstract

The let-7 target TRIM71/LIN-41 is a phylogenetically conserved RNA-binding protein best known as a heterochronic regulator of epidermal stem cell fate in C. elegans. I now show that TRIM71 is a novel marker of neuroepithelial cells, the earliest neural stem cells (NSCs) of the prenatal mammalian brain. Trim71 deletion in prenatal mouse NSCs (Nestin-Trim71fl/fl and Emx-Trim71fl/fl), or knock-in of a human congenital hydrocephalus-associated missense mutation that disrupts the regulation of target RNAs (Trim71R595H/+), causes severe cortical thinning and associated ventriculomegaly due to defective NSC self-renewal without altering ependymal cilia- driven cerebrospinal fluid flow. Strikingly, Trim71R595H/R595H mice exhibit anencephaly and embryonic lethality. These results define a single conserved residue in TRIM71 that is indispensable for mammalian brain morphogenesis and shed novel insight into the pathogenesis of the most common structural brain disorder in humans.

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