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Gametes are highly specialized cells for the creation of new individuals. To finally become functional gametes, the germ cell lineage including the precursors undergoes a unique series of differentiation processes orchestrated by genetic and epigenetic regulations. Conceptually, the process can be divided into two phases. In the first phase of differentiation, which is sex-independent, the cells propagate as a founder population while erasing epigenetic memories in the genome. In the second phase of differentiation, which is sex-dependent, the cells undergo remarkable morphological changes with de novo epigenetic modifications while halving the genome by meiosis. The first phase commences in primordial germ cells (PGCs) that are specified at an early stage of embryogenesis. Once PGCs are specified, they erase CpG methylation and begin to reorganize histone modifications at a genome-wide level. PGCs migrate towards the gonad while proliferating and acquire an “epigenetic ground state” upon settling in the gonad. The cell population is the founder for the subsequent second phase. During the first phase, there is no clear difference in gene expression and differentiation potency between males and females. In the second phase, however, differentiation becomes more complicated and interactive with surrounding somatic cells. Once entering the female gonad, PGCs enter meiosis (thereby becoming primary oocytes). At the perinatal stage, a majority of oocytes are eliminated by cell death and the remaining oocytes form primordial follicles that function as a storage of oocytes, ensuring the longevity of the reproductive life in the female. After puberty begins, some of the primordial follicles periodically undergo follicular development, which is characterized by proliferation of granulosa cells, maturation of theca cells and oocyte growth accompanied with de novo epigenetic modifications in the genome. When the oocyte growth reaches the plateau stage, meiosis resumes until it is arrested again at the meiotic metaphase II (MII) stage for fertilization. In the male gonad, on the other hand, PGCs are arrested at the G1 stage, and thereby become prospermatogonia. During the cell cycle arrest, the prospermatogonia acquire de novo epigenetic modifications. After birth, some of the prospermatogonia become spermatogonial stem cells (SSCs), which are crucial for sustaining spermatogenesis. After puberty begins, SSCs become differentiated types of spermatogonia, followed by spermatocytes, in which meiosis takes place to form haploid spermatids. By tight interaction with Sertoli cells, mature spermatozoa with tiny heads and long tails are formed from the spermatids.
One of the key goals in reproductive biology is to reconstitute all the processes of gametogenesis in culture, in order to produce a functional egg and sperm. Such in vitro gametogenesis will make it easy to analyze the complicated process of germ cell development. This may be particularly effective for the analysis of nascent PGCs, because the number of these cells is quite small in the embryos. In other words, in vitro gametogenesis could replace the use of experimental animals in accordance with the Animal Welfare Acts of various nations. From a more practical point of view, gametes produced by in vitro gametogenesis, termed in vitro gametes, could be an alternative source for animal reproduction, such as for the propagation of endangered animals. Moreover, once the capability for producing human in vitro gametes exists, their great potential utility will necessitate a discussion as to whether they should be used for human reproduction. Due to the unique capability of the germ cell lineage, in vitro gametogenesis has a huge impact on a wide range of research. Our recent progress in mice suggests that in vitro gametes are not a fantasy, but realistically achievable materials that will promote basic research and provide a practical strategy for reproduction. These achievements are based on accumulating knowledge on developmental biology, stem cell biology and cell culture technologies. Stem cells in particular are an essential material for realizing in vitro gametogenesis, since they can propagate indefinitely under certain conditions while maintaining their ability to differentiate.

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