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

Abstract

The development of male germ cells within the prenatal and prepubertal periods in mammals combines multiple biological events that integrate cell cycle regulation, epigenetic reprogramming, 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 G 0 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 spermatogonia. 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.

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

“…Using cell line models and whole-mouse testes, Zhang et al (2013a) reported that long and short transcripts of Kit are expressed in spermatogonia, the long transcript being mainly expressed in the cytoplasm and cell membrane, while the short transcript was found in nuclei as well as the cytoplasm and cell membrane. They also reported that the long transcript of Kit was not expressed in SSCs, in line with other studies (Payne 2013). This group concluded that there are extensive transcriptional and translational changes in KIT expression before and after SSCs differentiation (Zhang et al 2013a).…”

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

“…All told, we found that at least 33 known “migration genes” are regulated by Rhox10 . This was intriguing given that the migration of ProSG to the periphery of seminiferous tubules accompanies their differentiation into SSCs (Culty, 2009; Payne, 2013). The linkage of these two events, coupled with the finding that Rhox10 regulates batteries of migration genes and promotes SSC generation, led us to test whether Rhox10 has a role in ProSG migration.…”

“…Among them, Pdgfrb and Dab2ip , have been directly shown to drive ProSG migration in neonatal testes (Basciani et al, 2008; Xu et al, 2015). Of note, Pdgfrb not only promotes ProSG migration but also the accompanying step, resumption of ProSG proliferation (Basciani et al, 2008; Payne, 2013; Thuillier et al, 2010). Given that we obtained evidence that Rhox10 also acts on the same two developmental steps—promoting the differentiation of mitotically inactive ProSG (T1-ProSG) into mitotically active ProSG (T2-ProSG) and driving the migration of T2-ProSG into the SSC niche—it is tempting to speculate that Pdgfrb is a key effector gene downstream of RHOX10.…”

“…This migratory event is critical, as evidence suggests it places ProSG in the appropriate niche that allows them to become self-renewing SSCs (Payne, 2013). We postulate that by promoting the migration of cells to this stem cell niche, RHOX10 serves as a critical transcription factor that not only places SSCs in the appropriate environment for their long-term function as stem cells, but also drives their initial generation.…”

Stem-ing mTOR: p53 maintains the male germline

“…In rodents, the predominant model for this system consists of a putative stem cell referred to as an A single (A s ) spermatogonium, which divides to generate either 2 additional A s spermatogonia or interconnected A paired (A pr ) daughter cells that do not complete cytokinesis. 1 4 , Intermediate (In), and Type B differentiating spermatogonia before forming pre-leptotene spermatocytes that initiate entry into meiosis. Despite many years of research on male germline stem cell differentiation, this process has not been fully deciphered at the molecular level.…”