Abstract:
Loss of ovarian homeostasis is associated with ovary dysfunction and female diseases; however, the underlying mechanisms responsible for the establishment of homeostasis and its function in the ovary have not been fully elucidated. Here, we showed that conditional knockout of Rab37 in oocytes impaired macroautophagy/autophagy proficiency in the ovary and interfered with follicular homeostasis and ovary development in mice. Flunarizine treatment upregulated autophagy, thus rescuing the impairment of follicular homeostasis and ovarian dysfunction in rab37 knockout mice by reprogramming of homeostasis. Notably, both the E2F1 and EGR2 transcription factors synergistically activated Rab37 transcription and promoted autophagy. Thus, RAB37-mediated autophagy ensures ovary function by maintaining ovarian homeostasis.Abbreviations: AMH: anti-Mullerian hormone; ATG: autophagy related; BECN1: beclin 1; cKO: conditional knockout; Cre: cyclization recombination enzyme; dpp: days postpartum; E2: estradiol; E2F1: E2F transcription factor 1; EBF1: EBF transcription factor 1; EGR2: early growth response 2; FSH: follicle stimulating hormone; LH: luteinizing hormone; mpp: months postpartum; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; RAB37: RAB37, member RAS oncogene family; SQSTM1: sequestosome 1; TFEB: transcription factor EB; Zp3: zona pellucida glycoprotein 3.
摘要:
卵巢稳态的丧失与卵巢功能障碍和女性疾病有关;然而,在卵巢中建立稳态及其功能的潜在机制尚未完全阐明。这里,我们表明,卵母细胞中Rab37的条件性敲除会损害卵巢中的大型自噬/自噬能力,并干扰小鼠的卵泡稳态和卵巢发育。氟桂利嗪治疗上调自噬,因此,通过对稳态进行重编程,挽救了rab37基因敲除小鼠的卵泡稳态和卵巢功能障碍。值得注意的是,E2F1和EGR2转录因子协同激活Rab37转录并促进自噬。因此,RAB37介导的自噬通过维持卵巢稳态来确保卵巢功能。