WNT signaling in pre-granulosa cells is required for ovarian folliculogenesis and female fertility

Abstract

In mammalian ovaries, immature oocytes are reserved in primordial follicles until their activation for potential ovulation. Precise control of primordial follicle activation (PFA) is essential for reproduction, but how this is achieved is unclear. Here, we show that canonical wingless-type MMTV integration site family (WNT) signaling is pivotal for pre-granulosa cell (pre-GC) activation during PFA. We identified several WNT ligands expressed in pre-GCs that act in an autocrine manner. Inhibition of WNT secretion from pre-GCs/GCs by conditional knockout (cKO) of the wntless (Wls) gene led to female infertility. In Wls cKO mice, GC layer thickness was greatly reduced in growing follicles, which resulted in impaired oocyte growth with both an abnormal, sustained nuclear localization of forkhead box O3 (FOXO3) and reduced phosphorylation of ribosomal protein S6 (RPS6). Constitutive stabilization of β-catenin (CTNNB1) in pre-GCs/GCs induced morphological changes of pre-GCs from a squamous into a cuboidal form, though it did not influence oocyte activation. Our results reveal that canonical WNT signaling plays a permissive role in the transition of pre-GCs to GCs, which is an essential step to support oocyte growth.

Stage Specific Transcriptomic Analysis and Database for Zebrafish Oogenesis

“…Indeed, genes such as ctcf ( Wan et al, 2008 ), eIf4g ( Keiper 2019 ), alk4 ( Souquet et al, 2012 ), and hira ( Nashun et al, 2015 ; Burkhart et al, 2020 ) have all been shown to play essential roles in oocyte development and are maternally deposited. All other genes associated with this functional term are maternally deposited according to ZFIN expression data and include components of signaling pathways that pattern the early embryo such as Nodal and Wnt/β-cat ( Whitman 2001 ; Souquet et al, 2012 ; Fuentes et al, 2020 ; Habara et al, 2021 ) ( Supplementary Data sheet S2 ).…”

Single-cell transcriptomics of staged oocytes and somatic cells reveal novel regulators of follicle activation

“…Several of these targets have been characterized in follicle activation. For example, studies have identified the importance of WNT signaling in pre-granulosa to granulosa cell differentiation ( Ford et al 2021 , Habara et al 2021 ). Further, TGFB1 signaling mediates cell cycle arrest in pre-granulosa cells ( Hardy et al 2018 , Granados-Aparici et al 2019 ), and inhibiting TGFB1 signaling promotes follicle activation ( Wang et al 2014 ).…”

Characterization of circular RNA profiles of oviduct reveal the potential mechanism in prolificacy trait of goat in the estrus cycle

“…In the luteal phase (LL vs. LH), the host genes of chi_circ_0000475, chi_circ_0013463, chi_circ_0000659, and chi_circ_0010484 were RYK , ESR1 , EVA1C, and SMAD5 , respectively. RTK is a member of the WNT signalling pathway receptor, and WNT has multiple biological functions and is highly correlated with female fertility ( Habara et al, 2021 ). The estrogen receptor alpha gene ( ESR1 ) is involved in hormonal regulation, whereas luteal phase OECs are predominantly secretory cells and are involved in estrogen secretion ( Abe, 1996 ), and estrogen is an important regulator of reproduction ( Oh et al, 2017 ).…”