Roles ofStra8andTcerg1lin retinoic acid induced spermatogonial differentiation in mouse

Abstract

Retinoic acid (RA) induces spermatogonial differentiation, but the mechanism by which it operates remains largely unknown. We developed a germ cell culture assay system to study genes involved in spermatogonial differentiation triggered by RA. Stimulated by Retinoic Acid 8 (Stra8), a RA-inducible gene, is indispensable for meiosis initiation, and its deletion results in a complete block of spermatogenesis at the pre-leptotene/zygotene stage. To interrogate the role of Stra8 in RA mediated differentiation of spermatogonia, we derived germ cell cultures from the neonatal testis of both wild type and Stra8 knock-out mice. We provide the first evidence that Stra8 plays a crucial role in modulating the responsiveness of undifferentiated spermatogonia to RA and facilitates transition to a differentiated state. Stra8-mediated differentiation is achieved through downregulation of a large portfolio of genes and pathways, most notably including genes involved in the spermatogonial stem cell self-renewal process. We also report here for the first time the role of Transcription Elongation Regulator-1 Like (Tcerg1l) as a downstream effector of RA-induced spermatogonial differentiation.

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis

“…STRA8 expression is commonly used in the field as a proxy for RA signaling [33,38,[54][55][56][57]. Although the specific function of this putative transcription factor remains unclear, STRA8 is unique to germ cells and to vertebrates, and has been associated with expression of pluripotency-associated genes and meiotic initiation [56,58].…”

“…STRA8 expression is commonly used in the field as a proxy for RA signaling [33,38,[54][55][56][57]. Although the specific function of this putative transcription factor remains unclear, STRA8 is unique to germ cells and to vertebrates, and has been associated with expression of pluripotency-associated genes and meiotic initiation [56,58]. Interestingly, STRA8 is expressed in both type A 1 differentiating spermatogonia and preleptotene spermatocytes entering meiosis [33,54,55], although it is not required for either process.…”

SRSF2 is required for mRNA splicing and spermatogenesis

“…Retinoic acid (RA) is an important factor of spermatogenesis, with functions on spermatogonial differentiation and subsequently initiation of meiosis (41,42). switches to the second role and acts as a transcription activator of genes involved in meiosis initiation (43)(44)(45). In addition to RA signaling, Dazl is also regarded as a regulator of meiotic initiation (46).…”

“…On one hand, under the influence of RA, Stra8 functions as a transcriptional repressor of the pluripotency program during differentiation of spermatogonia. When differentiating spermatogonia are near the end of their mitotic phase, Stra8 switches to the second role and acts as a transcription activator of genes involved in meiosis initiation (43)(44)(45). In addition to RA signaling, Dazl is also regarded as a regulator of meiotic initiation (46).…”

Function of Retinoic Acid in Development of Male and Female Gametes

“…The results showed transcriptional changes at the time of spermatogonial differentiation, which likely accounted for the previously established meiotic failure in Stra8-null mice [ 26 ]. Another study reiterated these findings, using RNA-seq with an adapted culture technique, showing Stra8 functions in two roles: (1) as a transcriptional repressor prior to differentiation to downregulate pluripotency genes and (2) as a transcriptional activator to activate genes associated with pre-meiotic initiation [ 27 ]. These studies make the argument that RA-mediated activation of Stra8 regulates spermatogonia differentiation and pre-meiotic activation.…”