# Regulation of proliferation and differentiation in the male germ line adult stem cell lineage

> **NIH NIH R35** · STANFORD UNIVERSITY · 2022 · $14,095

## Abstract

PROJECT SUMMARY (of Parent Project):
 Regulation of proliferation and differentiation in the male germ line adult stem cell lineage
The switch from proliferation to differentiation is a key regulatory point in both embryonic development and the
adult stem cell lineages that underlie tissue maintenance and repair. Failure of this switch may contribute to
genesis of cancer. My laboratory has long used the Drosophila male germ line as a model to investigate how
self-renewal, proliferation and differentiation are regulated in adult stem cell lineages. Several lines of our inquiry
have recently begun to converge on the molecular mechanisms underlying the developmentally programmed
transition from mitotic proliferation to onset of meiosis and differentiation, implicating a number of molecular and
cellular mechanisms in regulating this critical switch. We find that RNA binding proteins involved in translational
control and alternative splicing act cell autonomously to regulate the cessation of proliferation and that
progression of differentiation requires communication from associated somatic support cells. We discovered
that a developmentally regulated switch in the site at which specific nascent transcripts are cut to form 3’ ends,
leading to production of novel mRNA isoforms with shortened 3’UTRs, controls dramatic changes in the suite of
proteins expressed in differentiating spermatocytes compared to proliferating spermatogonia. We found that
dramatic changes in chromatin open over 2000 new promoters with novel core sequence structure to turn on the
new cell type specific transcription program when cells initiate spermatocyte differentiation. Some of the earliest
genes turned on in this differentiation program encode chromatin associated proteins that prevent spurious
opening of normally cryptic promoters, thus preventing massive misexpression of genes associated with the
wrong cell type. Other transcripts upregulated with differentiation onset encode cell type-specific translational
regulators that delay production of core G2/M cell cycle machinery to program the extended G2 phase of meiotic
prophase. Over the next 5 years, we propose to map how these processes collaborate to form the regulatory
circuitry that initiates then executes the switch from mitosis to meiosis. We will investigate how the RNA binding
proteins Bam and Bgcn trigger the switch from mitosis to differentiation by repressing expression of the
alternative splice factor HOW, identify candidate substrates of HOW by immunoprecipitation followed by RNA-
Seq, and assess their function in vivo, including whether they communicate with adjacent somatic support cells.
We will investigate how the switch in proteins expressed due to alternative 3’ end cut site selection on nascent
transcripts is regulated and influences differentiation. We will investigate how cell-type specific chromatin
regulators and proteins that recruit them to specific loci set up the new transcription program for diff...

## Key facts

- **NIH application ID:** 10675340
- **Project number:** 3R35GM136433-03S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MARGARET T FULLER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $14,095
- **Award type:** 3
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10675340

## Citation

> US National Institutes of Health, RePORTER application 10675340, Regulation of proliferation and differentiation in the male germ line adult stem cell lineage (3R35GM136433-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10675340. Licensed CC0.

---

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