Developmental underpinnings of spermatogonial stem cell establishment

Abstract

Background: The germline serves as a conduit for transmission of genetic and epigenetic information from one generation to the next. In males, spermatozoa are the final carriers of inheritance and their continual production is supported by a foundational population of spermatogonial stem cells (SSCs) that forms from prospermatogonial precursors during the early stages of neonatal development. In mammals, the timing for which SSCs are specified and the underlying mechanisms guiding this process remain to be completely understood.

Objectives: To propose an evolving concept for how the foundational SSC population is established.

Materials and methods: This review summarizes recent and historical findings from peer-reviewed publications made primarily with mouse models while incorporating limited studies from humans and livestock.

Results and conclusion: Establishment of the SSC population appears to follow a biphasic pattern involving a period of fate programming followed by an establishment phase that culminates in formation of the SSC population. This model for establishment of the foundational SSC population from precursors is anticipated to extend across mammalian species and include humans and livestock, albeit on different timescales.

Keywords: establishment; germline; gonocyte; prospermatogonia; specification; spermatogonial stem cel.

FIGURE 1

Evolving biphasic model underlying formation of the foundational SSC population in mice. Mitotically active fetal prospermatogonia (Prosp^M) progressively enter quiescence leading up to E16.5 to form transitional Prospg (Prospg^T1). During the Programming phase, genes necessary for postnatal SSC function are upregulated in a subset of quiescent Prospg^T1, including Etv5, Id4, Gfra1, Lhx1, and Ret, while a different subset upregulates genes associated with progenitors or differentiation, including Sohlh1 and Sox3. Based on the outcomes from transplantation analyses, stem cell potential within the germline becomes confined to those Prosg^T1 that upregulate SSC-associated transcripts, indicating that postnatal fate is programmed during this time. After birth, the germline enters an Establishment phase. Prospg^T1asynchronously re-enter the cell cycle, which marks formation of Prospg^T2. A dramatic shift in gene expression also occurs, including upregulation of genes necessary for postnatal SSC function. Conclusion of the Establishment phase is marked by a brief period of self-renewal that builds the foundational SSC population from which continuous spermatogenesis will arise throughout adulthood. By contrast, Prospg programmed for non-SSC fate either enter the differentiating spermatogonial path directly to generate the first round of spermatogenesis or possibly form a population of initial progenitor-like germ cells that will be the source of a second round of spermatogenesis that does not emanate from the foundational SSC pool