December 22, 2020

New Insights into the transition from primordial to primary follicle: eight genes are sufficient for developing mouse oocyte-like cells from mouse stem cells

Nobuhiko Hamazaki, Katsukiko Hayashi and colleagues at Kyushu University in Fukuoka, Japan (1) have recently published work describing a number of detailed studies of the transition from mouse primordial to primary follicle oocyte growth. What is quite remarkable is that they report that eight genes are sufficient to allow mouse stem cells to develop directly into oocyte-like cells. These induced cells have abnormal chromosomal structure but were able to be fertilized and advance to the two cells stage of development. The reported studies provide scientists with methods to acquire oocyte cytoplasm that may be utilized for studies of reproductive biology. Insights from these studies have great potential for the development of treatments of mitochondrial replacement therapy to prevent the occurrence of diseases in children of mothers with mitochondrial defects.

Mammalian oocytes are specialized cells. The process of their development—oogenesis –is a long and highly regulated, complex process from embryonic stem cells to mature oocytes that are able to be fertilized by sperm and form a new individual. Briefly we know that in the embryo the cells that differentiate in the primordial germ cells migrate to the fetal gonads and become primordial ooctyes  within primordial follicles. There they remain dormant for months in the mouse and up to 40 to 50 years in humans. During puberty these primordial ooctyes enter meiosis to become primary oocytes. These cells arrest in the diplotene stage of meiosis at prophase 1 and are contained in the primary follicles of the ovary. Just prior to ovulation meiosis is reinstituted and the cells divide. The whole complex process of oocyte develpment involves a number of cell types, reciprocal interactions of the oocyte with the follicular cells, many nutrients, numerous cytokine combinations, growth factors and transcription factors acting in precise ways, many hormones, epigenetic changes, and meiosis to ensure cell division of the haploid number of species-specific chromosomes. Alterations in this process such as a lack of necessary transcription factors or inappropriate separation of the chromosomes will cause birth defects and other defects that harm the health of offspring and impair fertility. 

Therefore, reproductive scientists and physicians have long utilized model systems to study oogenesis as well as to understand infertility and the harmful alterations that impact on human health. A great deal has been learned from mouse models of oogenesis. More recently scientists have begun to develop techniques of in vitro oocyte maturation as a means to understand oogenesis more completely. This technique is used to preserve fertility in cancer patients. In their recently published work, Hamazaki, Hayashi and their colleagues identified eight genes for transcription factors that are essential for the primordial to primary oocyte transition. Remarkedly they also report that these eight factors are able to directly induce oocyte-like cells from pluripotent stem cells. Thus, they effectively bypassed the primordial follicular stage of development. They call these cells DIOL cells. The eight transcriptional factors genes are Lhx8, Sohln1, Nobox, Tbpl2 (which Hamazaki and Hayashi call the core network) and Stat3, Dynall1, Sub1 and Figla. The scientists also demonstrated that the pluripotent state was necessary to develop the DIOL cells. Despite abnormal chromosomal structure, these DIOL cells were able to be fertilized and develop to the two- cell stage. DNA demethylation was not a prerequisite to activate the gene-regulation network driving oocyte growth in their system. Others have suggested that the role epigenetic reprograming is in the activation of meiosis.(2-3) Thus, Hamazaki and Hayashi conclude that the control mechanisms of meiotic entry are distinct from oocyte growth. These studies reported by the Kyushu scientists are important in promoting a more complete understanding of the primordial to primary follicle transition and to the distinct regulation of oocyte growth at this stage from that regulation of meiosis.  By Phyllis Leppert

(1) Hamasaki N, Kyogoku H, Araki H, Miura F, Horikawa C, Hamada N, Shimamoto S, Hikabe O, Nakashima K, Kitajima TS, Ito T, Leitch HG, Hayashi K. Reconstitution of the oocyte transcriptional network with transcription factors. Nature. 2020, https://doi.org/10.1038/s4158-020-3027-9

(2) Yamaguchi S, Hong K, Liu R, Shen L, Inoue A, Diep A, Zhang K, Zhang Y.  Tet1 controls meiosis by regulating meiotic gene expression. Nature 2012 492: 443-447.

(3) Hill PWS, Leitch HG, Requena CE, Sun Z, Amouroux @, Roman-Trufero M, Vaisvila R, Linnett S, Bagci H, Dharmalingham G, Haberle V, Lenhard B, Zhang Y, Pradhan S, Hajkova P. Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature 2018 555: 392-396.