Core fucosylation regulates the ovarian response via FSH receptor during follicular development

Tiantong Wang; Zhiwei Zhang; Changduo Qu; Wanli Song; Ming Li; Xiaoguang Shao; Tomohiko Fukuda; Jianguo Gu; Naoyuki Taniguchi; Wenzhe Li

doi:10.1016/j.jare.2024.01.025

Core fucosylation regulates the ovarian response via FSH receptor during follicular development

J Adv Res. 2024 Jan 26:S2090-1232(24)00038-9. doi: 10.1016/j.jare.2024.01.025. Online ahead of print.

Authors

Tiantong Wang¹, Zhiwei Zhang², Changduo Qu³, Wanli Song⁴, Ming Li³, Xiaoguang Shao⁵, Tomohiko Fukuda², Jianguo Gu², Naoyuki Taniguchi⁶, Wenzhe Li⁷

Affiliations

¹ Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China; College of Basic Medical Sciences, Dalian Medical University, 9 West Section Lvshun South Road, Dalian, Liaoning 116044, China.
² Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi 981-8558, Japan.
³ College of Basic Medical Sciences, Dalian Medical University, 9 West Section Lvshun South Road, Dalian, Liaoning 116044, China.
⁴ Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China.
⁵ Medical Center for Reproductive and Genetic Research, Dalian Municipal Women and Children's Medical Center, 878 Xibei Road, Gezhenbao Street, Dalian, Liaoning 116037, China.
⁶ Department of Glyco-Oncology and Medical Biochemistry, Osaka International Cancer Institute, 3-1-69 Otemae, Chuoku, Osaka 541-8567, Japan.
⁷ Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong 515041, China; Shantou University Medical College, 22 Xinling Road, Shantou, Guangdong 515041, China. Electronic address: liwenzhe@stu.edu.cn.

PMID: 38280716
DOI: 10.1016/j.jare.2024.01.025

Abstract

Introduction: Ovarian low response to follicle-stimulating hormone (FSH) causes infertility featuring hypergonadotropic hypogonadism, ovarian failure, and/or defective ovarian response.

Objectives: N-glycosylation is essential for FSH receptor (FSHR). Core fucosylation catalyzed by fucosyltransferase 8 (FUT8) is the most common N-glycosylation. Core fucosylation level changes between individuals and plays important roles in multiple physiological and pathological conditions. This study aims to elucidate the significance of FUT8 to modulate FSHR function in female fertility.

Methods: Samples from patients classified as poor ovary responders (PORs) were detected with lectin blot and real-time PCR. Fut8 gene knockout (Fut8^-/-) mice and FUT8-knockdown human granulosa cell line (KGN-KD) were established and in vitro fertilization (IVF) assay, western blot, molecular interaction, immunofluorescence and immunoprecipitation were applied.

Results: Core fucosylation is indispensable for oocyte and follicular development. FSHR is a highly core-fucosylated glycoprotein. Loss of core fucosylation suppressed binding of FSHR to FSH, and attenuated FSHR downstream signaling in granulosa cells. Transcriptomic analysis revealed the downregulation of several transcripts crucial for oocyte meiotic progression and preimplantation development in Fut8^-/- mice and in POR patients. Furthermore, loss of FUT8 inhibited the interaction between granulosa cells and oocytes, reduced transzonal projection (TZP) formation and caused poor developmental competence of oocytes after fertilization in vitro. While L-fucose administration increased the core fucosylation of FSHR, and its sensitivity to FSH.

Conclusion: This study first reveals a significant presence of core fucosylation in female fertility control. Decreased fucosylation on FSHR reduces the interaction of FSH-FSHR and subsequent signaling, which is a feature of the POR patients. Our results suggest that core fucosylation controls oocyte and follicular development via the FSH/FSHR pathway and is essential for female fertility in mammals.

Keywords: Core Fucosylation; Female fertility; Follicle-stimulating hormone receptor (FSHR); Fucosyltransferase 8 (FUT8); Ovarian response.