Biology subjects

Hirate, Y.

Publications and source records attributed to Hirate, Y..

3 recordsLinked to original sources

bioRxiv2026

Selective depletion of AMH-expressing granulosa cells in vivo impairs follicular development and fertility in female mice

In mammals, ovarian follicle development is a highly coordinated process that underlies female fertility. Granulosa cells expressing anti-Mullerian hormone (AMH) are widely used as a marker of growing follicles. However, the in vivo roles of granulosa cells in follicular development and female fertility remain unclear. Here, we analyzed AMH-toxin receptor-mediated cell knockout (AMH-TRECK) transgenic (Tg) mice on a NOG background, in which AMH-expressing granulosa cells are specifically depleted by diphtheria toxin (DT). We first found that, after a single DT injection into postnatal AMH-TRECK Tg females, AMH-expressing granulosa cells in primary and secondary follicles exhibited cleaved caspase-3 signals 1 day later and were depleted 4 days later. Second, after repeated DT injections weekly from 1 to 7 weeks of age in AMH-TRECK Tg females, antral follicles and corpora lutea were rarely observed, and the numbers of primordial, primary, and secondary follicles were decreased. Following PMSG and hCG stimulation, repeated DT-injected Tg females exhibited a reduced number of ovulated oocytes with a low proportion of mature oocytes, resulting in reduced IVF rates and fertility. Further, after a cessation of repeated DT treatment, ovarian weight and follicular development recovered: the numbers of primary, secondary, and antral follicles were recovered, whereas the primordial follicle pool remains reduced. We conclude that selective depletion of AMH-expressing granulosa cells in vivo impairs follicular development and fertility. Our model enables assessment of the in vivo effects of granulosa cell depletion and may provide a useful platform for future transplantation-based studies to understand complex follicular dynamics.

developmental biology↗

bioRxiv2024

Targeting of retrovirus-derived Rtl8a/8b reduces social response and increases apathy-like behavior associated with GABRB2 reduction

Retrotransposon Gag-like (RTL) 8A, 8B and 8C are eutherian-specific genes derived from a certain retrovirus. They clustered as a triplet of genes on the X chromosome, but their function remains unknown. Here, we demonstrate that Rtl8a and Rtl8b play important roles in the brain: their double knockout (DKO) mice not only exhibit reduced social responses and increased apathy-like behavior, but also become obese from young adulthood. Mouse RTL8A/8B proteins are expressed in the prefrontal cortex and hypothalamus and localize to both the nucleus and cytoplasm of neurons, presumably due to the N-terminal nuclear localization signal-like sequence at the N-terminus. An RNAseq study in the cerebral cortex revealed reduced expression of several GABA type A receptor subunits, in particular the {beta}2 subunit of Gabrb2, in DKO. We confirmed the reduction of GABRB2 protein in the DKO cerebral cortex by Western blotting. As GABRB2 has been implicated in the etiology of several neurodevelopmental disorders, it is likely that the reduction of GABRB2 is one of the major causes of the neuropsychiatric defects in the DKO mice.

molecular biology↗

bioRxiv2023

Targeting retrovirus-derived Rtl8a and 8b causes late onset obesity and neurodevelopmental defects

Retrotransposon Gag-like (RTL) 8A, 8B and 8C are triplet genes of uncertain function that form a cluster on the X chromosome. They are eutherian-specific genes presumably derived from a certain retrovirus. Here, we demonstrate that Rtl8a and Rtl8b play an important role in growth and behavior via brain functions in the hypothalamus and prefrontal cortex. Rtl8a and Rtl8b double knockout (DKO) mice exhibited overgrowth due to hyperphagia from young adulthood and reduced social responses, increased apathy-like behavior. RTL8A and RTL8B proteins are localized to both the nucleus and cytoplasm of neurons presumably due to an N-terminal nuclear localization signal-like sequence. An increment in nucleus size was also detected in the neurons in the prefrontal cortex, suggesting neuronal dysfunction. These data give another strong evidence that retrovirus-derived acquired genes contributed to the establishment of the current eutherian developmental system in a wide variety of ways. Summary statementRtl8a and Rtl8b double knockout mice exhibited late onset obesity and neurodevelopmental defects, demonstrating that these eutherian specific retrovirus-derived acquired genes encoding proteins with only 113 amino acids play important roles in the brain presumably via their functions in the hypothalamus and prefrontal cortex.

molecular biology↗