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

Center for Human Embryonic Stem Cell Research and Education, Institute for Stem Cell Biology & Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford University, Palo Alto, California 94305, USA.
Nature (Impact Factor: 41.46). 11/2009; 462(7270):222-5. DOI: 10.1038/nature08562
Source: PubMed


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.

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Available from: Renee A Reijo Pera, Dec 05, 2014
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    • "In human ESCs cultured in vitro, over-expression of DAZ family proteins induced haploid cell formation. Concomitant with DAZL expression in hESCs, VASA expression was also induced, while knockdown of Dazl reduced VASA by ~50 % [38]. In addition, expression of pluripotent genes that are normally expressed in germline stem cells were also induced with the expression of DAZ proteins in ESCs, consistent with the notion that DAZ proteins regulate germ cell fate determination. "
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    ABSTRACT: Adult stem cells that reside in particular types of tissues are responsible for tissue homeostasis and regeneration. Cellular functions of adult stem cells are intricately related to the gene expression programs in those cells. Past research has demonstrated that regulation of gene expression at the transcriptional level can decisively alter cell fate of stem cells. However, cellular contents of mRNAs are sometimes not equivalent to proteins, the functional units of cells. It is increasingly realized that post-transcriptional and translational regulation of gene expression are also fundamental for stem cell functions. Compared to differentiated somatic cells, effects on cellular status manifested by varied expression of RNA-binding proteins and global protein synthesis have been demonstrated in several stem cell systems. Through the cooperation of both cis-elements of mRNAs and trans-acting RNA-binding proteins that are intimately associated with them, regulation of localization, stability, and translational status of mRNAs directly influences the self-renewal and differentiation of stem cells. Previous studies have uncovered some of the molecular mechanisms that underlie the functions of RNA-binding proteins in stem cells in invertebrate species. However, their roles in adult stem cells in mammals are just beginning to be unveiled. This review highlights some of the RNA-binding proteins that play important functions during the maintenance and differentiation of mouse male germline stem cells, the adult stem cells in the male reproductive organ.
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    • "DAZ and DAZ-like protein (DAZL) are expressed in germ cells and are essential for normal spermatogen- esis[Yen, 2004]. DAZ members are necessary for latestage meiosis and the development of haploid spermatids, whereas DAZL functions primarily in primordial germ cell formation[Kee et al., 2009]. Azoospermia associated with decreased DAZ may go along with reduced levels of SYCP3[Reynolds et al., 2007]. "
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    • "negative results. Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs), represent a unique system by which investigators can examine the effects of toxicants as these cells can be differentiated into any cell type in the adult organism, including germ cells[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]. Recently, we demonstrated that male human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) are directly differentiated into adult-type spermatogonial stem cells/spermatogonia, pre-meiotic and post-meiotic spermatocytes, and post-meiotic spermatids[5]. "
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