Enhanced Fitness of Adult Spermatogonial Stem Cells Bearing a Paternal Age-Associated FGFR2 Mutation
نویسندگان
چکیده
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.
منابع مشابه
The role of fibroblast growth factor receptor 2 (FGFR2) in differentiation of bovine spermatogonial stem cells (SSCs)
The receptors 1 and 2 of fibroblast growth factor (FGFR1 and FGFR2, respectively) have been observed in all types of testicular cells. Culture on extracellular matrix (ECM) has been observed to lead to initiation of differentiation in spermatogonial stem cells (SSCs). The present study was carried out to investigate whether FGFR1 and FGFR2 play a role in SSCs differentiation. Following isolatio...
متن کاملComparison of Neonatal and Adult Mice-derived Sertoli Cells in Support of Expansion of Mouse Spermatogonial Stem Cells In vitro
متن کامل
O-3: Identification and Characterization of Repopulating Spermatogonial Stem Cells from The Adult Human Testis
Background: This study was conducted to identify and characterize repopulating spermatogonial stem cells (SSCs) in the adult human testes. Materials and Methods: Testes biopsies from obstructive azoospermic patients and normal segments of human testicular tissue were used. Flow cytometry, real time PCR and immunohistochemical analysis were performed. Purified human spermatogonia were transplant...
متن کاملO-19: Proliferation of Small Population of Spermatogonial Stem Cells in Azoospermic Patients
Background: With treatment success in young boys with cancer, long-term effects of cancer treatment have found importance in pediatric oncology. Temporary or permanent infertility after treatment is an important subject in childhood and adult cancer patients which decrease quality of life. The one approach to overcome infertility in these cases is to cryopreserve small biopsy testicular tissue ...
متن کاملSelfish Spermatogonial Selection: Evidence from an Immunohistochemical Screen in Testes of Elderly Men
The dominant congenital disorders Apert syndrome, achondroplasia and multiple endocrine neoplasia-caused by specific missense mutations in the FGFR2, FGFR3 and RET proteins respectively-represent classical examples of paternal age-effect mutation, a class that arises at particularly high frequencies in the sperm of older men. Previous analyses of DNA from randomly selected cadaveric testes show...
متن کامل