Developmental origins of mammalian spermatogonial stem cells: New perspectives on epigenetic regulation and sex chromosome function*

Male and female germ cells undergo genome-wide reprogramming during their development, and execute sex-specific programs to complete meiosis and successfully generate healthy gametes. While sexually dimorphic germ cell development is fundamental, similarities and differences exist in the basic processes governing normal gametogenesis. At the simplest level, male gamete generation in mammals is centred on the activity of spermatogonial stem cells (SSCs), and an equivalent cell state is not present in females. Maintaining this unique SSC epigenetic state, while keeping to germ cell-intrinsic developmental programs, poses challenges for the correct completion of spermatogenesis. In this review, we highlight the origins of spermatogonia, comparing and contrasting them with female germline development to emphasize specific developmental processes that are required for their function as germline stem cells. We identify gaps in our current knowledge about human SSCs and further discuss the impact of the unique regulation of the sex chromosomes during spermatogenesis, and the roles of X-linked genes in SSCs.