Trim71/Lin-41 Links an Ancient miRna Pathway to Human Congenital Hydrocephalus

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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