Lhx8 ablation leads to massive autophagy of mouse oocytes associated with DNA damage†

Abstract

Following proliferation of oogonia in mammals, great numbers of germ cells are discarded, primarily by apoptosis, while the remainder form primordial follicles (the ovarian reserve) that determine fertility and reproductive lifespan. More massive, rapid, and essentially total loss of oocytes, however, occurs when the transcription factor Lhx8 is ablated-though the cause and mechanism of germ cell loss from the Lhx8-/-ovaries has been unknown. We found that Lhx8−/− ovaries maintain the same number of germ cells throughout embryonic development; rapid decrease in the pool of oocytes starts shortly before birth. The loss results from activation of autophagy, which becomes overwhelming within the first postnatal week, with extracellular matrix proteins filling the space previously occupied by follicles to produce a fibrotic ovary. Associated with this process, as early as a few days before birth, Lhx8-/-oocytes failed to repair DNA damage-which normally occurs when meiosis is initiated during embryonic development; and DNA damage repair genes were downregulated throughout the oocyte short lifespan. Based on gene expression analyses and morphological changes, we propose a model in which lineage-restricted failure of DNA repair triggers germ cell autophagy, causing premature depletion of the ovarian reserve in Lhx8-/-mice. Summary SentenceAblation of Lhx8 causes premature loss of germ cells by autophagy associated with impairment of DNA damage repair during meiosis.

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

“…This indicates that there exist other mechanisms responsible for extensive oocyte degeneration and follicles formation (Greenfeld, Pepling, Babus, Furth, & Flaws, ; Perez et al, ). Our study together with others have demonstrated that autophagy‐induced PCD of oocytes may be pivotal for oocyte loss and functional follicles formation in mice without affecting meiosis because the number of oocytes recovered after inhibiting autophagy was significantly higher than that of apoptosis (Ignazio et al, ; Rodrigues et al, ; Tu et al, ). Apoptosis appears to eliminate oocytes with genetic or meiotic pairing errors, while autophagy helps oocytes to form functional follicles.…”

Protective effects of silymarin on testis histopathology, oxidative stress indicators, antioxidant defence enzymes and serum testosterone in cadmium‐treated mice

“…Samples were cut into 7 µm sections by a cryostat (Leica, Germany). Sections were stained by Heidenhain's Azan method (D’Ignazio et al, ). In order to measure the diameter and wall thickness of seminiferous tubules as well as the nucleus diameter of the spermatogonia, the sections were photographed under light microscopy (Olympus, Japan) by a camera.…”

Identification of Biomarkers for Predicting Ovarian Reserve of Primordial Follicle via Transcriptomic Analysis

“…Then the RNA microarray dataset from Lhx8 knockout mice was included (GSE109473). It has been reported that Lhx8 knockout leads to massive depletion of the primordial follicle and induces OR depletion in mice ( Ren et al, 2015 ; D'Ignazio et al, 2018 ). The results showed that the expression of six genes, including Lhx8 , Sohlh1 , Nobox , Stk31 , Tbpl2 , and Padi6 , was significantly reduced in ovary tissues from Lhx8 knockout mice, while no probe of Vrtn was observed ( Figure 6B ).…”