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

Abstract

Defects in germ-cell (oocyte and sperm) development are a leading cause of infertility in men and women. Several studies have shown that germ cells can be differentiated from mouse and human embryonic stem cells, but human germ cells produced in this way generally fail to develop beyond the earliest stages and do not enter meiosis. Now a team from Stanford's Institute for Stem Cell Biology and Regenerative Medicine has developed a system in which primordial germ cells can be derived from both male and female human embryonic stem cells. By silencing and overexpressing germ-cell-specific genes, human germ-cell formation and developmental progression can be modulated. Specifically, the human DAZL gene, which is implicated in infertility, is shown to function in primordial germ-cell formation, whereas closely related family members, DAZ and BOULE, modulate later stages of meiosis and development of haploid male gametes. This system can be used to study germ-cell defects and the potential to correct them therapeutically. Defects in human germ-cell (oocyte and sperm) development are the leading cause of infertility in men and women. A germ-cell reporter is now used to quantify and isolate primordial germ cells derived from both male and female human embryonic stem cells. Human DAZL is observed to function in primordial germ-cell formation, whereas the closely related genes DAZ and BOULE promote later stages of meiosis and development of gametes. 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 stages1,2,3,4,5,6,7,8. 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.