Periodic production of retinoic acid by meiotic and somatic cells coordinates four transitions in mouse spermatogenesis

Abstract

SignificanceMale mouse sex cells mature into sperm through a 35-d process punctuated by four transitions, two occurring before meiosis (spermatogonial differentiation and meiotic initiation) and two after meiosis (spermatid elongation and sperm release). The four transitions occur in proximity spatially and temporally, with an 8.6-d periodicity. We describe how this coordination is achieved. The premeiotic transitions were known to be regulated by retinoic acid (RA). We show that RA also regulates the two postmeiotic transitions. RA levels change periodically, and meiotic cells contribute to its production. The two postmeiotic transitions require RA from meiotic cells while the premeiotic transitions require RA from somatic cells. These elements underpin the spatiotemporal coordination of spermatogenesis to ensure constant sperm production throughout adult life.

Undifferentiated spermatogonia regulateCyp26b1expression through NOTCH signaling and drive germ cell differentiation

“…RA is particularly critical for the transition between A undiff and differentiating germ cells because rats and mice deprived of dietary RA can only produce A undiff spermatogonia and are sterile (28). Further, RA activity is critical for initiation of the meiotic process and is also necessary for postmeiotic spermatid maturation (5,(29)(30)(31). As the availability of RA within the stem cell niche increases after birth, CYP26B1 in Sertoli cells must be down-regulated to allow spermatogonial differentiation and the first wave of spermatogenesis to take place.…”

“…As the availability of RA within the stem cell niche increases after birth, CYP26B1 in Sertoli cells must be down-regulated to allow spermatogonial differentiation and the first wave of spermatogenesis to take place. Further, low levels of CYP26B1 are still expressed and functionally relevant in adult Sertoli cells and must be modulated to allow the transition from A undiff to A 1 spermatogonia at stage VIII of the seminiferous epithelium (31,32). However, the mechanisms that modulate CYP26B1 enzyme production in the postnatal testis are poorly understood.…”

Open niche regulation of mouse spermatogenic stem cells

“…In accordance with the seminiferous epithelial cycle, the aforementioned signals affecting SSCs fluctuate temporally in the basal compartment, in the order of GDNF→Wnt6→RA→GDNF (Figure c) (Endo et al., ; Grasso et al., ; Hogarth et al., ; Ikami et al., ; Sato et al., ; Sharma & Braun, ; Sugimoto et al., ; Tokue et al., ; Vernet et al., ). The numbers of GFRα1 + , Ngn3 + , and Kit + cells also fluctuate during the cycle (Figure d).…”

“…Sertoli cells also express high levels of Wnt6 , a ligand of Wnt/beta‐catenin signal that supports the differentiation‐primed (Ngn3 + ) state of SSCs (Chassot et al., ; Takase & Nusse, ; Tokue et al., ). Sertoli cells also play an important role in the retinoic acid (RA) signal that promotes irreversible differentiation to Kit + spermatogonia, as Sertoli cells and different stages of germ cells cooperatively express the enzymes involved in the retinoid metabolism (Endo, Freinkman, De Rooij, & Page, ; Sugimoto, Nabeshima, & Yoshida, ; Vernet et al., ). According to in vitro studies using cultured spermatogonia and in vivo studies using transient transfection and bead implantation, fibroblast growth factor (FGF) is another important regulator of SSCs (Hasegawa & Saga, ; Kanatsu‐Shinohara et al., ; Masaki et al., ; Takashima et al., ).…”

“…to Kit + spermatogonia, as Sertoli cells and different stages of germ cells cooperatively express the enzymes involved in the retinoid metabolism (Endo, Freinkman, De Rooij, & Page, 2017;Sugimoto, Nabeshima, & Yoshida, 2012;Vernet et al, 2006). According to in vitro studies using cultured spermatogonia and in vivo studies using transient transfection and bead implantation, fibroblast growth factor (FGF) is another important regulator of SSCs (Hasegawa & Saga, 2014;Kanatsu-Shinohara et al, 2003;Masaki et al, 2018;Takashima et al, 2015).…”