The genes of cell death and cellular susceptibility to apoptosis in the ovary: a hypothesis

Recent advances in the field of cell death, primarily derived from gene-transfer experiments and manipulation of tumor cell lines in vitro, have identified key genes responsible for determining whether or not a given cell will initiate apoptosis. However, comparatively less is known of the role that the products of these genes play in physiological settings of cell death. In the ovary, a tremendous level of normal cell death takes place in the germline throughout the later stages of fetal development. This process is responsible for setting the absolute number of oocytes ('eggs') available for subsequent development and ovulation during adult life. Interestingly, death remains the fate of the vast majority of oocytes that survive the waves of attrition during fetal life and are endowed in the post-natal ovary as primordial follicles. This pool of oocytes is lost indirectly as a consequence of the death of the somatic (granulosa) cells that, in the case of a small percentage of the total follicles, support and nourish the oocyte until its release at ovulation. Due to the magnitude of cell death that occurs normally within the female gonad during both fetal development and post-natal life, the ovary has proven to be an excellent model to study the role of cell death genes in a physiological setting of endocrine-regulated apoptosis. It is now known that a diverse spectrum of pro- and anti-apoptosis susceptibility genes, including members of the bcl-2 and CASP (ced-3/Ice) gene families, are expressed in germ cells and/or somatic cells of the ovary. Many, but not all, of these genes are regulated by specific survival factors, such as gonadotropins and growth factors, and changes in the temporal patterns of cell death gene expression suggest an intimate association exists between the products of these genes and activation of cellular suicide. Moreover, pathological oocyte destruction, such as that triggered by exposure of female germ cells to chemotherapeutic compounds or environmental toxicants, may also be dependent upon gene-driven apoptosis. As such, this review will discuss data supporting the hypothesis that the susceptibility of ovarian cells to death induction is dependent upon the pattern of cell death gene expression occurring within those cells prior to and/or concomitant with receipt of the stimulus for apoptosis. Elucidation of the relationship between germ cell loss and cell death genes may allow future intervention into the process of oocyte depletion associated with normal and pathophysiological reproductive senescence.     

Pluripotent stem cells: Maintenance of genetic and epigenetic stability and prospects of cell technologies

Permanent lines of pluripotent stem cells can be obtained from humans and monkeys using different techniques and from different sources—inner cell mass of the blastocyst, primary germ cells, parthenogenetic oocytes, and mature spermatogonia—as well as by transgenic modification of various adult somatic cells. Despite different origin, all pluripotent lines demonstrate considerable similarity of the major biological properties: active self-renewal and differentiation into various somatic and germ cells in vitro and in vivo, similar gene expression profiles, and similar cell cycle structure. Ten years of intense studies on the stability of different human and monkey embryonic stem cells demonstrated that, irrespective of their origin, long-term in vitro cultures lead to the accumulation of chromosomal and gene mutations as well as epigenetic changes that can cause oncogenic transformation of cells. This review summarizes the research data on the genetic and epigenetic stability of different lines of pluripotent stem cells after long-term in vitro culture. These data were used to analyze possible factors of the genome and epigenome instability in pluripotent lines. The prospects of using pluripotent stem cells of different origin in cell therapy and pharmacological studies were considered.     

RSPO1/β-catenin signaling pathway regulates oogonia differentiation and entry into meiosis in the mouse fetal ovary

Differentiation of germ cells into male gonocytes or female oocytes is a central event in sexual reproduction. Proliferation and differentiation of fetal germ cells depend on the sex of the embryo. In male mouse embryos, germ cell proliferation is regulated by the RNA helicase Mouse Vasa homolog gene and factors synthesized by the somatic Sertoli cells promote gonocyte differentiation. In the female, ovarian differentiation requires activation of the WNT/β-catenin signaling pathway in the somatic cells by the secreted protein RSPO1. Using mouse models, we now show that Rspo1 also activates the WNT/β-catenin signaling pathway in germ cells. In XX Rspo1(-/-) gonads, germ cell proliferation, expression of the early meiotic marker Stra8, and entry into meiosis are all impaired. In these gonads, impaired entry into meiosis and germ cell sex reversal occur prior to detectable Sertoli cell differentiation, suggesting that β-catenin signaling acts within the germ cells to promote oogonial differentiation and entry into meiosis. Our results demonstrate that RSPO1/β-catenin signaling is involved in meiosis in fetal germ cells and contributes to the cellular decision of germ cells to differentiate into oocyte or sperm.     

小鼠胚胎干细胞向生殖细胞分化的研究

小鼠胚胎干细胞(ESC)在体外可以分化为多种细胞类型,其中包括各阶段的生殖细胞,甚至精细胞和成熟卵母细胞。ESC向生殖细胞分化的效率受到包括生长因子、激素和体细胞等多种因素的影响,在体外形成的是雌性配子还是雄性配子与ESC是XX型还是XY型没有必然联系。简要综述了小鼠生殖细胞在体内外的分化发育、性别决定和增殖等,并总结和展望了ESC向生殖细胞分化研究面临的问题和应用前景。