Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate
Glial cell-line derived neurotrophic factor-mediated RET signaling regulates spermatogonial stem cell fate
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DOI：
10.1095/biolreprod.105.047365
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发表时间：
2006-02-01
影响因子：
3.6
通讯作者：
Milbrandt, J
中科院分区：
文献类型：
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作者：
Naughton, CK;Jain, S;Milbrandt, J
正常的精子发生对生殖是必不可少的，并且依赖于适当的精原干细胞（SSC）功能。调节SSC功能的基因和信号通路尚未得到很好的定义。我们报道胶质细胞源性神经营养因子（GDNF）信号通过RET酪氨酸激酶/GFRA 1受体复合物是小鼠精原细胞自我更新所必需的。GFRA 1和RET表达在出生时的生殖细胞亚群中被鉴定，仅限于正常精子发生期间的SSC，并且RET表达细胞在SSC自我更新的隐睾模型中丰富。我们使用的全睾丸移植技术，以克服的限制，新生儿死亡的GDNF，GFRA 1，和视网膜缺陷小鼠，发现这些基因都是出生后精子发生所需的，而不是胚胎睾丸发育。每个突变体睾丸在生精第一波期间，到出生后第7天显示出严重的SSC耗竭。这些缺陷是由于缺乏SSC增殖和SSC不能维持未分化状态。我们的研究结果表明，GDNF介导的RET信号是未分化的精原细胞的命运，这一途径的异常可能有助于男性不育和睾丸生殖细胞肿瘤的关键。
Normal spermatogenesis is essential for reproduction and depends on proper spermatogonial stem cell (SSC) function. Genes and signaling pathways that regulate SSC function have not been well defined. We report that glial cell-line-derived neurotrophic factor (GDNF) signaling through the RET tyrosine kinase/GFRA1 receptor complex is required for spermatogonial self-renewal in mice. GFRA1 and RET expression was identified in a subset of gonocytes at birth, was restricted to SSCs during normal spermatogenesis, and RET expressing cells were abundant in a cryptorchid model of SSC self-renewal. We used the whole-testis transplantation technique to overcome the limitation of neonatal lethality of Gdnf-, Gfra1-, and Ret-deficient mice and found that each of these genes is required for postnatal spermatogenesis and not for embryological testes development. Each mutant testis shows severe SSC depletion by Postnatal Day 7 during the first wave of spermatogenesis. These defects were due to lack of SSC proliferation and an inability of SSCs to maintain an undifferentiated state. Our results demonstrate that GDNF-mediated RET signaling is critical for the fate of undifferentiated spermatogonia and that abnormalities in this pathway may contribute to male infertility and testicular germ cell tumors.