# Conserved regulation of the switch from proliferation to differentiation in the germ line stem cell lineage

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $316,199

## Abstract

Project Summary / Abstract
Conserved regulation of the switch from proliferation to differentiation in the germ line stem cell lineage
The switch from proliferation to differentiation is a key regulatory point in adult stem cell lineages, crucial for
tissue maintenance and repair. Failure of this switch may contribute to genesis of cancer. Here we study the
molecular mechanisms underlying a developmentally programmed transition from proliferation to differentiation
in the germ cell lineage, where the switch from mitosis to meiosis is a defining event. Drosophila bgcn
encodes an RNA binding protein required cell autonomously for spermatogonia to stop proliferation and enter
meiosis. We created mice null mutant for the mouse homolog of bgcn and discovered that genetic
mechanisms that underlie a clean switch from mitosis to meiosis are deeply conserved from Drosophila to
mammals. Male germ cells in Bgcn mutant mice execute the spermatogonial mitotic divisions and initiate
meiosis, turning on Stra8 and undergoing premeiotic DNA replication, but fail to stably implement the program
for meiotic prophase. Instead the nascent spermatocytes show only low or transient expression of number of
meiotic markers, fail to properly turn off several mitotic transcripts, prematurely enter an ectopic mitosis, then
die. We propose to capitalize on these discoveries to map the regulatory circuitry controlling the switch from
mitosis to meiosis in Drosophila males and explore how a homologous RNA binding protein, acting with
different partners, enforces a clean switch from the mitotic program to the meiotic program in mammals.
Using the short life span and powerful genetic tools in Drosophila, we identified the main target of repression
by Bgcn and its co-factor Bam for the switch to meiosis as the RNA binding protein HOW, homolog of
mammalian Quaking. We will investigate if Drosophila Bgcn and Bam directly regulate HOW mRNA translation
or stability, mapping the HOW mRNA sequences required for these regulators to bind. To discover how HOW
maintains the spermatogonial state, we will test the hypothesis that HOW prevents expression of a TGFB-class
ligand required to signal to somatic cells that the germ cells are ready to progress. In parallel, in an unbiased
approach to identify candidate substrates of HOW we will analyze RNA-Seq data to identify transcripts
alternatively spliced in spermatogonia vs spermatocytes that have conserved HOW binding sites, test whether
they co-immunoprecipitate with HOW from spermatogonia, then assess function in spermatogonia by genetic
assays in Drosophila. To discover how mammalian Bgcn ensures an effective switch from mitosis to meiosis,
we will investigate whether mBgcn targets mitotic transcripts that we discovered it binds for destruction or
translational repression in young spermatocytes. To investigate how Bgcn, with its partner Meioc, may act
indirectly to allow stable accumulation of meiotic transcripts, we will test a model based...

## Key facts

- **NIH application ID:** 9856489
- **Project number:** 5R01GM122951-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MARGARET T FULLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,199
- **Award type:** 5
- **Project period:** 2018-05-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856489

## Citation

> US National Institutes of Health, RePORTER application 9856489, Conserved regulation of the switch from proliferation to differentiation in the germ line stem cell lineage (5R01GM122951-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9856489. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*