Stromal Senp1 promotes mouse early folliculogenesis by regulating BMP4 expression

Abstract

BackgroundMammalian folliculogenesis, maturation of the ovarian follicles, require both growth factors derived from oocyte and surrounding cells, including stromal cells. However, the mechanism by which stromal cells and derived factors regulate oocyte development remains unclear.ResultsWe observed that SENP1, a small ubiquitin-related modifier (SUMO)-specific isopeptidase, was expressed in sm22α-positive stromal cells of mouse ovary. The sm22α-positive stromal cells tightly associated with follicle maturation. By using the sm22α-specific Cre system, we show that mice with a stromal cell-specific deletion of SENP1 exhibit attenuated stroma-follicle association, delayed oocyte growth and follicle maturation with reduced follicle number and size at early oocyte development, leading to premature ovarian failure at late stages of ovulating life. Mechanistic studies suggest that stromal SENP1 deficiency induces down-regulation of BMP4 in stromal cells concomitant with decreased expression of BMP4 receptor BMPR1b and BMPR2 on oocytes.ConclusionsOur data support that protein SUMOylation-regulating enzyme SENP1 plays a critical role in early ovarian follicle development by regulating gene expression of BMP4 in stroma and stroma-oocyte communication.Electronic supplementary materialThe online version of this article (doi:10.1186/s13578-017-0163-5) contains supplementary material, which is available to authorized users.

CD34+KLF4+ Stromal Stem Cells Contribute to Endometrial Regeneration and Repair

“…Scale bars: 20 mm (A and E) and 2.0 mm (C). number and size during early oocyte development, leading to premature ovarian failure in late stages of ovulating life (Tan et al, 2017). However, here, we demonstrate that estradiol can stimulate endometrial hyperplasia in ovariectomized SENP1smKO mice, eliminating the possibility that these effects derive from the ovary.…”

“…We observe endometrial hyperplasia and even endometrial cancer in aged SENP1smKO mice. Previously in SENP1smKO mice, we have observed delayed oocyte growth and follicle maturation with reduced follicle number and size during early oocyte development, leading to premature ovarian failure in late stages of ovulating life ( Tan et al, 2017 ). However, here, we demonstrate that estradiol can stimulate endometrial hyperplasia in ovariectomized SENP1smKO mice, eliminating the possibility that these effects derive from the ovary.…”

“…Smooth muscle 22a (SM22a) specific SENP1 knockout mice and tomato reporter mice Senp1 fl/fl mice were generated by inserting loxP sites surrounding the Senp1 gene exons 5 and 6, based on homologous recombination. Senp1 fl/fl mice were mated with a deleter line carrying the Cre recombinase driven by the Sm22a-promoter (sm22a-Cre:B6.129S6-Tagln tm2(cre)Yec /J purchased from the Jackson Laboratory) (Qiu et al, 2017;Shao et al, 2015;Tan et al, 2017;Yu et al, 2010;Zhu et al, 2017). For the reporter mice, the SM22a-Cre deleter mice were mated with mT/mG reporter mice (ROSA-26Sor tm4(ACTB-tdTomato, EGFP)Luo /J; purchased from The Jackson Laboratory) to generate sm22a:mT/mG mice.…”

Single‐cell RNA‐Seq reveals a highly coordinated transcriptional program in mouse germ cells during primordial follicle formation

“…BMP members BMP4 and BMP7 have been reported to promote primordial to primary follicle transition and a BMP4 antibody dramatically reduces the number of primordial follicles in the rat (Lee et al, 2004; Nilsson & Skinner, 2003). Recently, one study showed stromal cell‐specific knockout Senp1 , a small ubiquitin‐related modifier (SUMO)‐specific isopeptidase, attenuated follicle formation by markedly downregulated expression of BMP4 (Tan et al, 2017). Here, our study not only identified Bmpr1b as the DE gene and Id2 as the key regulon in oocytes but also demonstrated the regulation of BMPs on ID2 through the PI3K/mTOR signaling pathway.…”

Effect of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogels on frozen‐thawed human ovarian tissue in a xenograft model

“…Progrowing, primordial follicles do not have an independent capillary network, and they depend on their proximal stromal vessels . Not only vessels, but also stromal cells themselves are involved in promoting early folliculogenesis . Stromal cells have been described to have an important role in follicular survival and growth .…”