title: Enhanced fitness of adult spermatogonial stem cells bearing a paternal age-associated FGFR2 mutation.
abstract: Pathogenic 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.
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Martin
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Assif
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Moses
authors.initials: M
authors.lastname: Gilbert
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Dinali
authors.initials: D
authors.lastname: Wijewarnasuriya
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: mseandel@med.cornell.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Seandel
mesh_terms: D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010331:Paternal Age; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000378:metabolism; D013093:Spermatogonia / Q000166:cytology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D013737:Testis / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D051497:Receptor, Fibroblast Growth Factor, Type 2