DENND1A Desensitizes Granulosa Cells to FSH by Arresting Intracellular FSHR Transportation

Genome-wide association studies (GWAS) have identified polycystic ovary syndrome (PCOS)-associated loci, including DENND1A encoding a clathrin-binding protein involved in vesicle transport as a guanine nucleotide exchange factor. The effect of DENND1A on reproduction and whether it participates in follicle development disorder and androgen synthesis in PCOS remain unknown. Here, we demonstrated that DENND1A expression increased in ovarian granulosa cells (GCs) of PCOS patients and was positively correlated with serum testosterone concentration. We constructed a systemic transgenic Dennd1a mouse (TG mouse) model, which showed subfertility, irregular estrous cycles, and increased production of testosterone after PMSG stimulation. Moreover, TG mice showed hyporesponsiveness to PMSG with smaller ovary size and less well-developed follicles. Intracellular follicle-stimulating hormone receptor (FSHR) transport was disturbed by overexpression of Dennd1a, which promoted FSHR internalization and inhibited its recycling. Our findings revealed the reproductive function of DENND1A and the underlying mechanisms, which provided new insights into the PCOS pathogenesis and contributing to drug design for PCOS treatment. In our study it was shown that a markedly FSH insensitivity is responsible for low fertility in Dennd1a transgenic mouse compared to wild type mouse. Ovaries from 3 animals of the wild type and transgenic mouse were respectively collected at the injection of 44 hours of PMSG and processed for mRNA-seq analysis.