# Negative feedback regulation of growth factor signaling in adult spermatogonial stem cells

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $364,425

## Abstract

Abstract
Niche-derived growth factors (GFs) are essential for establishing and maintaining mammalian
spermatogonial stem cells (SSCs) in the adult testis. In culture, however, optimal conditions for
expansion of pure populations of self-renewing SSCs remain elusive. We recently found that
mouse SSCs possess unexpectedly robust mechanisms to counter-regulate GF signaling by
inducing expression of negative feedback regulators (NFRs), including members of the Spry
and Dusp gene families. Abrogation of specific NFRs in SSCs led to increase ERK signaling,
decreased expression of stem cell-associated genes in vitro and loss of stem cell activity upon
transplantation, suggesting that excessive GF-dependent signaling is detrimental to SSC
function and may favor differentiation. The cellular alterations that occur following perturbation
of NFRs are unknown. However, our data imply that SSCs are programmed to limit ERK
signaling within a narrow physiological range. This proposal addresses the mechanisms by
which NFRs restrict GF signaling in SSCs, prevent unscheduled differentiation, and enable
long-term propagation of SSC clones. Using genetic mouse models, SSC culture,
transplantation analysis, and a newly-developed real-time biosensor for ERK activity, we
address the following questions: (1) Which NFRs are required for SSC self-renewal? (2) How
does ablation of NFRs result in loss of stem cell activity? (3) How do NFRs control the dynamic
intracellular signaling cascades downstream of GF receptors? And (4) At which nodes in the
ERK pathway do NFRs exert their actions? In addition to providing a rational basis to improve
SSC culture systems, these studies will also identify novel adult SSC markers and shed light on
mechanisms by which cross-talk between the niche and SSCs balances self-renewal and
differentiation in vivo.

## Key facts

- **NIH application ID:** 10120177
- **Project number:** 1R01HD101452-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Marco Seandel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $364,425
- **Award type:** 1
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120177

## Citation

> US National Institutes of Health, RePORTER application 10120177, Negative feedback regulation of growth factor signaling in adult spermatogonial stem cells (1R01HD101452-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10120177. Licensed CC0.

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