Hartman Institute for Therapeutic Organ Regeneration

SPRY4-dependent ERK negative feedback demarcates functional adult stem cells in the male mouse germline†.

TitleSPRY4-dependent ERK negative feedback demarcates functional adult stem cells in the male mouse germline†.
Publication TypeJournal Article
Year of Publication2023
AuthorsLuo Y, Yamada M, N'Tumba-Byn T, Asif H, Gao M, Hu Y, Marangoni P, Liu Y, Evans T, Rafii S, Klein OD, Voss HU, Hadjantonakis A-K, Elemento O, Martin LA, Seandel M
JournalBiol Reprod
Date Published2023 Oct 13
KeywordsAdult Stem Cells, Animals, Cell Differentiation, Extracellular Signal-Regulated MAP Kinases, Feedback, Intercellular Signaling Peptides and Proteins, Male, Mammals, Mice, Spermatogonia

<p>Niche-derived growth factors support self-renewal of mouse spermatogonial stem and progenitor cells through ERK MAPK signaling and other pathways. At the same time, dysregulated growth factor-dependent signaling has been associated with loss of stem cell activity and aberrant differentiation. We hypothesized that growth factor signaling through the ERK MAPK pathway in spermatogonial stem cells is tightly regulated within a narrow range through distinct intracellular negative feedback regulators. Evaluation of candidate extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK)-responsive genes known to dampen downstream signaling revealed robust induction of specific negative feedback regulators, including Spry4, in cultured mouse spermatogonial stem cells in response to glial cell line-derived neurotrophic factor or fibroblast growth factor 2. Undifferentiated spermatogonia in vivo exhibited high levels of Spry4 mRNA. Quantitative single-cell analysis of ERK MAPK signaling in spermatogonial stem cell cultures revealed both dynamic signaling patterns in response to growth factors and disruption of such effects when Spry4 was ablated, due to dysregulation of ERK MAPK downstream of RAS. Whereas negative feedback regulator expression decreased during differentiation, loss of Spry4 shifted cell fate toward early differentiation with concomitant loss of stem cell activity. Finally, a mouse Spry4 reporter line revealed that the adult spermatogonial stem cell population in vivo is demarcated by strong Spry4 promoter activity. Collectively, our data suggest that negative feedback-dependent regulation of ERK MAPK is critical for preservation of spermatogonial stem cell fate within the mammalian testis.</p>

Alternate JournalBiol Reprod
PubMed ID37552049
PubMed Central IDPMC10577279
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 HD101452 / HD / NICHD NIH HHS / United States

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Hartman Institute for Therapeutic Organ Regeneration
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