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.

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

“…Thus, genes involved in SSC self-renewal will be briefly mentioned below, because of their use in isolating SSCenriched spermatogonia and characterizing SSCs, and because some of their gene products were shown to actively repress spermatogonial differentiation. Among the most frequently cited SSC markers are the GDNF receptors GFRa1 and RET, alongside OCT4 (POU5-F1/OCT3/4), PLZF (promyelocytic leukemia zinc finger; ZBTB16/ZFP145), LIN28A, BCL6B, NGN3, ID4, CDH1, UTF1, and SALL4 (reviewed by Nagano & Yeh (2013) and Song & Wilkinson (2014)). In contrast to the regulation of SSC maintenance, there are fewer proteins that have been implicated in the process of spermatogonial differentiation, such as the RA receptor RARg, and the RA-induced proteins STRA8 and KIT, SOHLH1 and SOHLH2, shown to be upregulated during SSC differentiation (Oatley & Brinster 2012).…”

Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling

“…The well-defined glial cell line-derived neurotrophic factor (GDNF) is a soluble factor that is secreted by Sertoli cells and influences the self-renewal of SSCs while inhibiting their differentiation (Meng et al 2000). The generation and characterization of male total and conditional AR knockout mice from different laboratories demonstrate the exceeding necessity of Sertoli cell-expressed AR signaling for meiosis (review in Wang et al (2009) transcriptional regulation of spermatogonial differentiation and spermatocyte meiosis by intrinsic factors (Rossi & Dolci 2013, Song & Wilkinson 2014. Thus, in this review, we focus on Sertoli cellcontrolled paracrine signaling during early stages of spermatogenesis.…”

ZBTB16: a novel sensitive and specific biomarker for yolk sac tumor

“…Infertility is observed in Zbtb16-null mice due to the impairment of spermatogonial stem cell self-renewal and subsequent exhaustion of spermatogonia. 28,29 Although the function of ZBTB16 in spermatogenesis is relatively well studied, expression of ZBTB16 in germ cell tumor has not yet been reported. The aim of this study was to investigate the immunohistochemical detection of ZBTB16 in testicular cells with particular focus on its diagnostic utility in germ cell tumor.…”