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DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation.
- Source :
-
Science China. Life sciences [Sci China Life Sci] 2024 Aug; Vol. 67 (8), pp. 1620-1634. Date of Electronic Publication: 2024 Apr 23. - Publication Year :
- 2024
-
Abstract
- Polycystic ovary syndrome (PCOS) is a complex disorder. Genome-wide association studies (GWAS) have identified several genes associated with this condition, including DENND1A. DENND1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular transport. However, the specific role of DENND1A in reproductive hormone abnormalities and follicle development disorders in PCOS remain poorly understood. In this study, we investigated DENND1A expression in ovarian granulosa cells (GCs) from PCOS patients and its correlation with hormones. Our results revealed an upregulation of DENND1A expression in GCs from PCOS cases, which was positively correlated with testosterone levels. To further explore the functional implications of DENND1A, we generated a transgenic mouse model overexpressing Dennd1a (TG mice). These TG mice exhibited subfertility, irregular estrous cycles, and increased testosterone production following PMSG stimulation. Additionally, the TG mice displayed diminished responsiveness to FSH, characterized by smaller ovary size, less well-developed follicles, and abnormal expressions of FSH-priming genes. Mechanistically, we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor (FSHR), promoting its internalization and inhibiting recycling. These findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms, thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.<br /> (© 2024. Science China Press.)
- Subjects :
- Animals
Female
Humans
Mice
Testosterone metabolism
Protein Transport
Receptors, FSH genetics
Receptors, FSH metabolism
Granulosa Cells metabolism
Follicle Stimulating Hormone metabolism
Polycystic Ovary Syndrome metabolism
Polycystic Ovary Syndrome genetics
Mice, Transgenic
Guanine Nucleotide Exchange Factors metabolism
Guanine Nucleotide Exchange Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1869-1889
- Volume :
- 67
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Science China. Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 38709439
- Full Text :
- https://doi.org/10.1007/s11427-023-2438-4