# Role of TRIM71 in neural stem cell biology and congenital hydrocephalus

> **NIH NIH F30** · YALE UNIVERSITY · 2021 · $30,891

## Abstract

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.

## Key facts

- **NIH application ID:** 10313612
- **Project number:** 1F30HD106694-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Duy Phan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,891
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313612

## Citation

> US National Institutes of Health, RePORTER application 10313612, Role of TRIM71 in neural stem cell biology and congenital hydrocephalus (1F30HD106694-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10313612. Licensed CC0.

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