Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark; International Research and Research Training Centre in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Blegdamsvej 9, 2100 Copenhagen, Denmark.
MRC Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Cell Rep. 2018 Nov 13;25(7):1924-1937.e4. doi: 10.1016/j.celrep.2018.10.064.
Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin.
干扰人类胎儿睾丸发育被广泛认为是睾丸生殖细胞癌（TGCC）起源和睾丸发育不良综合征（TDS）内其他疾病的基础。然而，人类睾丸发育不良的机制尚不清楚。我们使用离体培养和异种移植方法研究了 Nodal 和 Activin 信号在人类胎儿睾丸发育中的重要性。Nodal 信号的抑制，在某种程度上 Activin 信号的抑制，破坏了精曲小管的形成，使 AMH 表达消失，雄激素分泌减少，生殖细胞数量减少。随后的睾丸组织异种移植挽救了对精曲小管和体细胞的破坏作用，但对生殖细胞没有作用。Nodal 信号的刺激增加了表达多能性因子的生殖细胞数量，这些细胞在异种移植后仍然存在。我们的研究结果表明，Nodal 信号在调节生殖细胞分化和早期人类睾丸发育中起着关键作用，这对理解 TGCC 和 TDS 的起源具有重要意义。
