Transcriptional control of spermatogonial maintenance and differentiation

Abstract

Spermatogenesis is a multistep process that generates millions of spermatozoa per day in mammals. A key to this process is the spermatogonial stem cell (SSC), which has the dual property of continually renewing and undergoing differentiation into a spermatogonial progenitor that expands and further differentiates. In this review, we will focus on how these proliferative and early differentiation steps in mammalian male germ cells are controlled by transcription factors. Most of the transcription factors that have so far been identified as promoting SSC self-renewal (BCL6B, BRACHYURY, ETV5, ID4, LHX1, and POU3F1) are upregulated by glial cell line-derived neurotrophic factor (GDNF). Since GDNF is crucial for promoting SSC self-renewal, this suggests that these transcription factors are responsible for coordinating the action of GDNF in SSCs. Other transcription factors that promote SSC self-renewal are expressed independently of GDNF (FOXO1, PLZF, POU5F1, and TAF4B) and thus may act in non-GDNF pathways to promote SSC cell growth or survival. Several transcription factors have been identified that promote spermatogonial differentiation (DMRT1, NGN3, SOHLH1, SOHLH2, SOX3, and STAT3); some of these may influence the decision of an SSC to commit to differentiate while others may promote later spermatogonial differentiation steps. Many of these transcription factors regulate each other and act on common targets, suggesting they integrate to form complex transcriptional networks in self-renewing and differentiating spermatogonia.

Keywords: Differentiation; Self-renewal; Spermatogonia; Spermatogonial stem cell; Transcription factor.

Figure 1. The three regulatory steps of spermatogonial development

Not pictured is the fact that SSCs are a subset of undifferentiated A_s spermatogonia (and probably also A_pr and A_al4 spermatogonia).

Figure 2. Signaling pathway upstream of SSC maintenance factors

Transcription factors that promote SSC maintenance are shown in green boxes. The signaling pathways depicted as upregulating these transcription factors act by increasing the expression of the genes encoding them. An asterisk denotes a case where the subcellular localization of a transcription factor is altered by a signaling pathway.

Figure 3. Transcriptional regulatory networks

Green boxes denote factors that promote SSC maintenance. Purple boxes denote factors that promote SSC/spermatogonial differentiation. Known regulatory relationships are designated with solid arrows/lines; predicted regulatory relationships are denoted with dotted arrows/lines.