Enhanced Fitness of Adult Spermatogonial Stem Cells Bearing a Paternal Age-Associated FGFR2 Mutation

• FGFR2-mediated signaling regulates SSC self-renewal
• Age-associated Apert syndrome FGFR2 mutation confers a fitness advantage to SSCs
• Mutant FGFR2 enables SSCs to withstand limiting GDNF
• Excessive growth factor exposure impairs SSC self-renewal signals

SummaryPathogenic de novo mutations increase with fathers’ age and could be amplified through competition between genetically distinct subpopulations of spermatogonial stem cells (SSCs). Here, we tested the fitness of SSCs bearing wild-type human FGFR2 or an Apert syndrome mutant, FGFR2 (S252W), to provide experimental evidence for SSC competition. The S252W allele conferred enhanced FGFR2-mediated signaling, particularly at very low concentrations of ligand, and also subtle changes in gene expression. Mutant SSCs exhibited improved competitiveness in vitro and increased stem cell activity in vivo upon transplantation. The fitness advantage in vitro only occurred in low concentrations of fibroblast growth factor (FGF), was independent of FGF-driven proliferation, and was accompanied by increased response to glial cell line-derived neurotrophic factor (GDNF). Our studies provide experimental evidence of enhanced stem cell fitness in SSCs bearing a paternal age-associated mutation. Our model will be useful for interrogating other candidate mutations in the future to reveal mechanisms of disease risk.

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