Transforming growth factor-\u03b2 is involved in maintaining oocyte meiotic arrest by promoting natriuretic peptide type C expression in mouse granulosa cells

Jing Yang,Jia Li,Xiaoting Xu,Yu Zhang,Feifei Yuan,Meijia Zhang,Shumin Bo,Jie Qiao,Youqiang Su,Guoliang Xia

doi:10.1038/s41419-019-1797-5

Abstract

Natriuretic peptide type C (NPPC) secreted by mural granulosa cells (MGCs) maintains oocyte meiotic arrest via the activation of guanylyl cyclase-linked natriuretic peptide receptor 2 (NPR2). Here, we investigated the effect of transforming growth factor (TGF)-β on NPPC expression in MGCs and oocyte maturation. TGF-β ligands (TGFB1 and TGFB3, but not TGFB2) and receptors (TGFBR1 and TGFBR2) were predominantly expressed in MGCs. The activation of the follicle-stimulating hormone (FSH) receptor by FSH/equine chorionic gonadotropin (eCG) increased the levels of TGFB1, TGFBR2, and TGF-β downstream SMAD proteins in MGCs, which were decreased following the activation of the luteinizing hormone (LH) receptor by human chorionic gonadotropin (hCG). TGF-β significantly increased the gene and protein levels of NPPC in cultured MGCs through SMAD3 binding to Nppc promoter regions. In the presence of FSH, TGF-β further increased NPPC levels and inhibited oocyte meiotic resumption of cumulus-oocyte complexes (COCs). Moreover, Tgfbr2-specific depletion in granulosa cells using Fshr-Cre mice reduced NPPC mRNA and protein levels, resulting in the weak maintenance of oocyte meiotic arrest within large antral follicles. Tgfbr2 depletion also impaired follicle development, ovulation, and female fertility. Taken together, TGF-β-promoted NPPC in MGCs is involved in maintaining oocyte meiotic arrest. FSH and LH could regulate NPPC levels in MGCs via TGF-β and then control the process of oocyte meiosis.

Highlights

Mammalian oocyte meiosis begins in the fetal period but is arrested at the diplotene stage of the first meiotic prophase around the time of birth for a prolonged period[1,2]
TGFB1, TGFB3, TGFBR1, and TGFBR2 were clearly detected in the cytoplasm of mural granulosa cells (MGCs) and cumulus cells, and TGFB1 and TGFBR1 staining were weak in the oocyte cytoplasm (Fig. 1a)
TGFB2 mRNA and protein levels were dramatically higher in oocytes than in MGCs and cumulus cells, which are consistent with the immunofluorescence results (Fig. 1b, c)

Summary

Introduction

Mammalian oocyte meiosis begins in the fetal period but is arrested at the diplotene stage of the first meiotic prophase around the time of birth for a prolonged period[1,2]. Yang et al Cell Death and Disease (2019)10:558 by LH/human chorionic gonadotropin (hCG, a pregnancy hormone that exhibits LH activity) leads to a decrease in NPPC/NPR2 levels[11,12,13,14], and NPR2 activity by dephosphorylation and a reduction in NPPC-binding affinity[15,16,17]. All of these factors reduce the production of cGMP, thereby relieving cGMP-mediated inhibition of meiotic arrest[7,8].

Methods

Results

Conclusion