Interplay between Caspase 9 and X-linked Inhibitor of Apoptosis Protein (XIAP) in the oocyte elimination during fetal mouse development

Abstract

Abstract Mammalian female fertility is limited by the number and quality of oocytes in the ovarian reserve. The number of oocytes is finite since all germ cells cease proliferation to become oocytes in fetal life. Moreover, 70–80% of the initial oocyte population is eliminated during fetal and neonatal development, restricting the ovarian reserve. Why so many oocytes are lost during normal development remains an enigma. In Meiotic Prophase I (MPI), oocytes go through homologous chromosome synapsis and recombination, dependent on formation and subsequent repair of DNA double strand breaks (DSBs). The oocytes that have failed in DSB repair or synapsis get eliminated mainly in neonatal ovaries. However, a large oocyte population is eliminated before birth, and the cause or mechanism of this early oocyte loss is not well understood. In the current paper, we show that the oocyte loss in fetal ovaries was prevented by a deficiency of Caspase 9 (CASP9), which is the hub of the mitochondrial apoptotic pathway. Furthermore, CASP9 and its downstream effector Caspase 3 were counteracted by endogenous X-linked Inhibitor of Apoptosis (XIAP) to regulate the oocyte population; while XIAP overexpression mimicked CASP9 deficiency, XIAP deficiency accelerated oocyte loss. In the CASP9 deficiency, more oocytes were accumulated at the pachytene stage with multiple γH2AFX foci and high LINE1 expression levels, but with normal levels of synapsis and overall DSB repair. We conclude that the oocytes with LINE1 overexpression were preferentially eliminated by CASP9-dependent apoptosis in balance with XIAP during fetal ovarian development. When such oocytes were retained, however, they get eliminated by a CASP9-independent mechanism during neonatal development. Thus, the oocyte is equipped with multiple surveillance mechanisms during MPI progression to safe-guard the quality of oocytes in the ovarian reserve.