胶质细胞源性神经营养因子引发精原干细胞自我更新的信号通路

胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)是TGF-β超家族的一个相关成员。哺乳动物睾丸曲细精管内支持细胞分泌的GDNF,能促进精原干细胞(spermatogonial stem cells,SSCs)的自我更新与增殖。SSCs去分化诱导产生的多能干细胞已被广泛应用于再生医学领域,且SSCs在制作转基因动物、男性不育治疗和体外实施精子发生过程等方面,具有极大的应用价值。所以,GDNF引发SSCs自我更新的作用机理非常值得探索。通过对GDNF引发SSCs自我更新的信号通路进行系统梳理,我们发现了如下的作用过程:GDNF与GFR-α1特异性结合,活化Ret蛋白酪氨酸激酶,随后激活Ras/ERK1/2、PI3K-Akt和SFK信号通路,促进SSCs的自我更新;同时,在该过程中还存在信号通路间的交联对话现象。

The Signaling Pathway of Spermatogonial Stem Cells Self-Renewal Induced by Glial Cell Line-Derived Neurotrophic Factor

Glial cell line-derived neurotrophic factor(GDNF) is a related member of transformation growth factor beta(TGF-β) superfamily.GDNF is secreted by the sertoli cells in the mammalian testis seminiferous tubes,which promote self-renewal and proliferation of spermatogonial stem cells(SSCs).The SSCs are of great application value to prepare pluripotent stem cells by inducing dedifferentiation of SSCs,which are widely used in the field of regenerative medicine.They are also important in the production of transgenic animals,the treatment of male infertility,the spermatogenesis in vitro and so on.Therefore,the mechanism of self-renewal of SSCs caused by GDNF is worth to explore.The signaling pathways that GDNF participate in leading to SSCs self-renewal are reviewed systematically.A conclusion is reached ultimately: the GDNF signal molecule binds to GFR-α1 specifically and mediates activation of the Ret protein-tyrosine kinase(PTK),then the PTK activates Ras/ERK1/2,PI3K-Akt and SFK(Src-family kinase) signaling pathway,which ultimately promote SSCs self-renewal,and cross-talk phenomenon exists between the signaling pathways.