# Molecular regulation of germline development

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $553,916

## Abstract

PROJECT SUMMARY/ABSTRACT
 Our goal is to understand molecular principles of germ cell regulation. We focus on a decision that all stem
cells make: to self-renew or begin differentiation. This decision is fundamental in all tissues and is critical to
human health. Regulators that promote the stem cell state must be active to drive self-renewal and totipotency,
but must be inactivated for differentiation; conversely, regulators that are critical for differentiation must be
inactive in stem cells, but then become activated at the right time and place for differentiation. Regulation of the
transition – from self-renewal to differentiation – balances the two states and is fundamental to development,
homeostasis and human health. Defects in that balance cause human disease, including tissue atrophy and
cancer.
 RNA regulation is a major conserved theme in germ cells from worms to mammals. Key RNA-binding proteins
regulate self-renewal and differentiation across animal phylogeny. We focus on PUF (Pumilio and FBF) RNA-
binding proteins, which have pivotal roles in germ cells and neurobiology across animal species. In humans,
defective PUF proteins cause infertility and epilepsy. PUF proteins have many features in common: They sculpt
the transcriptome and proteome by binding to more than 1000 mRNAs, with 100's conserved between
nematodes and humans; they regulate target mRNAs by diverse mechanisms, including activation and
repression; and they work in a combinatorial fashion with partner proteins, most of which are also conserved.
 The challenge now is to understand how PUF proteins regulate the balance between self-renewal and
differentiation in molecular terms and in a native in vivo context. Our proposal addresses this challenge with a
sharp focus on four issues. First, we elucidate how distinct PUF mechanisms – activation and repression – work
together to control germ cell fates. Second, we elucidate how PUF partnerships operate in vivo, to understand
their logic and glean general principles. Third, we elucidate regulation of the balance between self-renewal to
differentiation. Fourth, we elucidate how a functional module of multiple PUF proteins and partners maintains
stem cells under diverse physiological and environmental conditions. These four issues are fundamental to all
PUF regulation. For each, we take a multidisciplinary and multiscale approach and exploit an exceptionally
tractable network. Together, our findings will advance our understanding germ cell regulation with potential for
broad impact, including of new therapy designs for humans.

## Key facts

- **NIH application ID:** 10017263
- **Project number:** 5R01GM134119-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** JUDITH KIMBLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $553,916
- **Award type:** 5
- **Project period:** 2019-09-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10017263

## Citation

> US National Institutes of Health, RePORTER application 10017263, Molecular regulation of germline development (5R01GM134119-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10017263. Licensed CC0.

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