Huwe1 Regulates the Establishment and Maintenance of Spermatogonia by Suppressing DNA Damage Response
Huwe1 Regulates the Establishment and Maintenance of Spermatogonia by Suppressing DNA Damage Response
复制标题
Huwe1 通过抑制 DNA 损伤反应来调节精原细胞的建立和维持。
DOI：
10.1210/en.2017-00396
复制
发表时间：
2017-11-01
期刊：
影响因子：
4.8
通讯作者：
Wing, Simon S.
中科院分区：
文献类型：
--
作者：
Fok, Kin Lam;Bose, Rohini;Wing, Simon S.
精子发生是由包括精原干细胞在内的异质性精原细胞群维持的。然而，其建立从生殖细胞胚胎前体和他们的维护之后的机制仍然在很大程度上未知。在这项研究中，我们报告，小鼠雄性生殖细胞中的泛素连接酶Huwe 1的失活导致新生儿精原细胞的变性，并导致成年人的Sertoli细胞表型。Huwe 1基因敲除的生殖母细胞有丝分裂再进入减少，这抑制了它们向精原细胞的转变。Huwe 1在初级精原细胞培养物或C18-4细胞系中失活导致细胞变性。Huwe 1基因敲除精原细胞的退化与组蛋白H2 AX水平的增加和DNA损伤反应的升高相关，这导致了明显的有丝分裂灾难，但不是凋亡或衰老。阻断H2 AX的这种增加可以防止Huwe 1缺失细胞的退化。总之，这些结果揭示了Huwe 1在男性生殖细胞中的生理DNA损伤反应中的一个先前未定义的作用，该反应有助于精原细胞的建立和维持。
Spermatogenesis is sustained by a heterogeneous population of spermatogonia that includes the spermatogonial stem cells. However, the mechanisms underlying their establishment from gonocyte embryonic precursors and their maintenance thereafter remain largely unknown. In this study, we report that inactivation of the ubiquitin ligase Huwe1 in male germ cells in mice led to the degeneration of spermatogonia in neonates and resulted in a Sertoli cell-only phenotype in the adult. Huwe1 knockout gonocytes showed a decrease in mitotic re-entry, which inhibited their transition to spermatogonia. Inactivation of Huwe1 in primary spermatogonial culture or the C18-4 cell line resulted in cell degeneration. Degeneration of Huwe1 knockout spermatogonia was associated with an increased level of histone H2AX and an elevated DNA damage response that led to apparent mitotic catastrophe but not apoptosis or senescence. Blocking this increase in H2AX prevented the degeneration of Huwe1-depleted cells. Taken together, these results reveal a previously undefined role of Huwe1 in orchestrating the physiological DNA damage response in the male germline that contributes to the establishment and maintenance of spermatogonia.