# Fmr1 Function and Repeat Expansion in the Developing Germline

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $435,875

## Abstract

PROJECT ABSTRACT
The goal of this proposal is to connect the events of fetal germ cell development to the origin and inheritance of
mutations in the Fmr1 locus, which are associated with Fragile X diseases. Evidence suggests that Fmr1
trinucleotide repeat expansions occur during development of germ cells, however the precise timing of Fmr1
repeat expansions, mechanism for intergenerational transmission, and function of the Fmr1 protein (FMRP) in
this lineage remains unclear, as few studies have examined the entire pool of gametes or their precursors.
Mouse models of Fmr1 deficiency as well as Fmr1-PM provide an opportunity to elucidate these mechanisms
in development. Our preliminary data support a role for Fmr1 in protecting the genomic integrity of fetal germ
cells and suggest that the period of scheduled apoptosis of fetal germ cells acts in divergent ways in the testis
versus the ovary. The studies proposed here will test the overall hypothesis that the development of fetal germ
cells provides a window of opportunity for Fmr1-PM amplifications based on the function of Fmr1 in genomic
integrity, but on the other hand development selects against the intergenerational transmission of germ cells
with amplifications in the male germline as compared to the female germline. Fragile X syndrome, along with
other trinucleotide repeat diseases, has been called a `double-edged sword' because the pathological repeat
expansion occurs in a gene required for DNA repair. In Aim 1, we will investigate the function of FMRP in
protecting the integrity of developing germ cells and identify its RNA targets. Given the evidence that
pathological CGG amplification occurs during Fmr1 transcription, these studies will provide critical insight into
the periods of vulnerability to Fmr1 repeat amplification during germ cell development. Although the size of
inherited Fmr1 pre-mutations increases with maternal age, this information is derived from successfully used
oocytes, whereas nothing is known about the entire gamete pool. In Aim 2, we will test the hypothesis that
FMRP1 increases fidelity of meiosis I in fetal oogonia whereas Fmr1 CGG repeat expansions interfere with
meiosis and compromise the quality of oocytes in the adult. These studies will elucidate the relationship
between Fmr1 pre-mutation, oocyte quality, and the dynamics of meiotic entry in the fetal ovary. In Aim 3 we
will use both Crispr-based imaging and next generation sequencing to reveal the impact of massive waves of
apoptosis that occur during normal male and female germ cell development on the diversity of repeat
expansions in Fmr1 pre-mutation mice. These studies will provide insight into the developmental origin of
pathological Fmr1 repeat expansions and potentially other mutations.

## Key facts

- **NIH application ID:** 10065433
- **Project number:** 5R01GM122902-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Diana J Laird
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,875
- **Award type:** 5
- **Project period:** 2017-12-26 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065433

## Citation

> US National Institutes of Health, RePORTER application 10065433, Fmr1 Function and Repeat Expansion in the Developing Germline (5R01GM122902-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10065433. Licensed CC0.

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