Bridge Integrator 2, a New Specific Target for Improving Reproductive Life Span through RPS6 and NNT

Female ovary is the earliest degenerated organ and it faces distinct medical disadvantages that impair primordial follicle reserve and oocyte quality. Herein, we found that bridge integrator 2 (Bin2) was predominant within mouse ovaries and oocytes, and global-knockout of Bin2 improved both female fertility and oocyte quality with healthy physiology in mice. Ovarian quantitative proteomics and phosphomics showed that Bin2 knockout specifically decreased only p-RPS6 of mTOR pathway; meanwhile, it increased nicotinamide nucleotide transhydrogenase (NNT), the free-radical detoxifier, over 6-fold. Mechanically, phosphorylation at Thr423 & Ser424 translocated membrane Bin2 into cytoplasm to phosphorylate RPS6, while p-RPS6 bound 42-95 bp NNT UTR to inhibit NNT translation. We then synthesized a peptide (BPP) to mimic Bin2 inhibition, and found that 3-week BPP injection improved primordial follicle reserve and oocyte quality in aging or chemotherapeutics-treated mice. In all, Bin2 inhibition improve both primordial follicle reserve and oocyte quality without discernible side effects.

Sequencing of the black rockfish chromosomal genome provides insight into sperm storage in the female ovary

Black rockfish (Sebastes schlegelii) is an economically important viviparous marine teleost in Japan, Korea, and China. It is characterized by internal fertilization, long-term sperm storage in the female ovary, and a high abortion rate. For better understanding the mechanism of fertilization and gestation, it is essential to establish a reference genome for viviparous teleosts. Herein, we used a combination of Pacific Biosciences sequel, Illumina sequencing platforms, 10× Genomics, and Hi-C technology to obtain a genome assembly size of 848.31 Mb comprising 24 chromosomes, and contig and scaffold N50 lengths of 2.96 and 35.63 Mb, respectively. We predicted 39.98% repetitive elements, and 26,979 protein-coding genes. S. schlegelii diverged from Gasterosteus aculeatus ∼32.1-56.8 million years ago. Furthermore, sperm remained viable within the ovary for up to 6 months. The glucose transporter SLC2 showed significantly positive genomic selection, and carbohydrate metabolism-related KEGG pathways were significantly up-regulated in ovaries after copulation. In vitro suppression of glycolysis with sodium iodoacetate reduced sperm longevity significantly. The results indicated the importance of carbohydrates in maintaining sperm survivability. Decoding the S. schlegelii genome not only provides new insights into sperm storage; additionally, it is highly valuable for marine researchers and reproduction biologists.

Biomarkers of Ovarian Reserve

The primary function of the female ovary is the production of a mature and viable oocyte capable of fertilization and subsequent embryo development and implantation. At birth, the ovary contains a finite number of oocytes available for folliculogenesis. This finite number of available oocytes is termed “the ovarian reserve”. The determination of ovarian reserve is important in the assessment and treatment of infertility. As the ovary ages, the ovarian reserve will decline. Infertility affects approximately 15%–20% of reproductive aged couples. The most commonly used biomarker assay to assess ovarian reserve is the measurement of follicle stimulating hormone (FSH) on day 3 of the menstrual cycle. However, anti-müllerian hormone and inhibin-B are other biomarkers of ovarian reserve that are gaining in popularity since they provide direct determination of ovarian status, whereas day 3 FSH is an indirect measurement. This review examines the physical tools and the hormone biomarkers used to evaluate ovarian reserve.