Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation

摘要

The leading cause of infertility in men and women is quantitative and qualitative defects in human germ-cell (oocyte and sperm) development. Yet, it has not been possible to examine the unique developmental genetics of human germ-cell formation and differentiation owing to inaccessibility of germ cells during fetal development. Although several studies have shown that germ cells can be differentiated from mouse and human embryonic stem cells, human germ cells differentiated in these studies generally did not develop beyond the earliest stages. Here we used a germ-cell reporter to quantify and isolate primordial germ cells derived from both male and female human embryonic stem cells. By silencing and overexpressing genes that encode germ-cell-specific cytoplasmic RNA-binding proteins (not transcription factors), we modulated human germ-cell formation and developmental progression. We observed that human DAZL (deleted in azoospermia-like) functions in primordial germ-cell formation, whereas closely related genes DAZ and BOULE (also called BOLL) promote later stages of meiosis and development of haploid gametes. These results are significant to the generation of gametes for future basic science and potential clinical applications.%生殖细胞(卵母细胞和精子)的发育缺陷是造成rn男性和女性不育症的一个主要原因。几项研究rn都表明，生殖细胞可从小鼠及人类胚胎干细胞rn分化出来，但以这种方式产生的人类生殖细胞rn的发育一般都不能超过最早阶段，不能进入减rn数分裂。现在，来自斯坦福大学干细胞生物学rn和再生医学研究所的一个研究小组培育出这样rn一个体系，在该体系中，原始生殖细胞从人类rn男性和女性胚胎干细胞都可形成。通过使生殖rn细胞特异性基因沉默和过度表达，可对人类rn生殖细胞的形成和发育进程进行调控。具体来rn说，人类DAZL基因(与不育症有关)被发现在rn原始生殖细胞形成中发挥功能，在该过程中两rn个密切相关的家族成员DAZ和BOULE调节单倍rn体男性配子减数分裂和发育的后期阶段。这个rn体系可被用来研究生殖细胞缺陷及通过治疗手rn段纠正它们的潜力。