Factors within the Developing Embryo and Ovarian Microenvironment That Influence Primordial Germ Cell Fate

Background: Primordial germ cell (PGC) fate is dictated by the designation, taxis, and influence of the surrounding embryonic somatic cells. Whereas gonadal sex determination results from a balance of factors within the tissue microenvironment. Summary: Our understanding of mammalian ovary development is formed in large part from developmental time courses established using murine models. Genomic tools where genes implicated in the PGC designation or gonadal sex determination have been modulated through complete or conditional knockouts in vivo, and studies in in situ models with inhibitors or cultures that alter the native gonadal environment have pieced together the interplay of pioneering transcription factors, co-regulators and chromosomes critical for the progression of PGCs to oocytes. Tools such as pluripotent stem cell derivation, genomic modifications, and aggregate differentiation cultures have yielded some insight into the human condition. Additional understanding of sex determination, both gonadal and anatomical, may be inferred from phenotypes that arise from de novo or inherited gene variants in humans who have differences in sex development. Key Messages: This review highlights major factors critical for PGC specification and migration, and in ovarian gonad specification by reviewing seminal murine models. These pathways are compared to what is known about the human condition from expression profiles of fetal gonadal tissue, use of human pluripotent stem cells, or disorders resulting from disease variants. Many of these pathways are challenging to decipher in human tissues. However, the impact of new single-cell technologies and whole-genome sequencing to reveal disease variants of idiopathic reproductive tract phenotypes will help elucidate the mechanisms involved in human ovary development.