Cycling to and from a stem cell niche: The temporal and spatial odyssey of mitotic male germ cells

The development of male germ cells within the prenatal and prepubertal periods in mammals combines multiple biological events that integrate cell cycle regulation, epigenetic re-programming, and cell migration along temporally and spatially dynamic lines. Germ cells arise from their precursor primordial germ cells in the mid-gestation embryo, forming gonocytes that enter G₀ phase cell cycle arrest within the fetal testis. Cyclin-dependent kinase inhibitors, activated retinoblastoma 1 protein, and increased levels of transforming growth factor beta 2 collectively influence this cell cycle arrest. Gonocyte quiescence persists until shortly after birth, whereupon the cells concomitantly re-enter the cell cycle and migrate towards a niche that establishes and maintains self-renewing spermatogonial stem cells and balances them with differentiating sper-matogonia. Platelet-derived growth factor signaling is one of the mechanisms that regulates both mitotic activation and migration in neonatal gonocytes, along with mitogens, 17b-estradiol and retinoic acid, and chemoattractants C-C-motif ligand 9 and members of the ADAM, integrin, and tetraspanin families. Numerous germ cell-intrinsic proteins have been identified that ensure the retention of germ cells within the spermatogonial stem cell niche. Sertoli cells are a significant component of this niche, contributing essential growth factors and chemokines to spermatogonia. This review focuses on the dynamic events that occur to mitotic male germ cells before and during their arrival at this niche, with an emphasis on the cell cycle and directed migration.