Enhanced Fitness of Adult Spermatogonial Stem Cells Bearing a Paternal Age-Associated FGFR2 Mutation
Enhanced Fitness of Adult Spermatogonial Stem Cells Bearing a Paternal Age-Associated FGFR2 Mutation
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DOI：
10.1016/j.stemcr.2014.06.007
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发表时间：
2014-08-12
影响因子：
5.9
通讯作者：
Seandel, Marco
中科院分区：
文献类型：
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作者：
Martin, Laura A.;Assif, Nicholas;Seandel, Marco
致病性从头突变随着父亲年龄的增长而增加，并且可以通过遗传上不同的精原干细胞（SSC）亚群之间的竞争而放大。在这里，我们测试了携带野生型人类 FGFR2 或阿佩尔综合征突变体 FGFR2 (S252W) 的 SSC 的适应性，为 SSC 竞争提供实验证据。 S252W 等位基因增强了 FGFR2 介导的信号传导，特别是在配体浓度极低的情况下，并且还导致基因表达发生微妙的变化。突变的SSC在移植后表现出提高的体外竞争力和增加的体内干细胞活性。体外适应性优势仅发生在低浓度的成纤维细胞生长因子（FGF）中，与 FGF 驱动的增殖无关，并且伴随着对胶质细胞系源性神经营养因子（GDNF）的反应增加。我们的研究提供了携带父系年龄相关突变的 SSC 中干细胞适应性增强的实验证据。我们的模型将有助于将来询问其他候选突变以揭示疾病风险机制。
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.