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.
Highlights
The number of oocytes in the ovarian reserve is finite since all germ cells cease proliferation to become oocytes in fetal life
We have previously reported that oocyte loss in fetal ovaries is prevented by a deficiency of Caspase 9 (CASP9), which is the hub of the mitochondrial apoptotic pathway[19]
We have previously reported a larger oocyte population retained in Casp9−/− ovaries compared to Casp9+/+
Summary
The number of oocytes in the ovarian reserve is finite since all germ cells cease proliferation to become oocytes in fetal life. 70–80% of the initial oocyte population gets eliminated during fetal and neonatal development, restricting the ovarian reserve. The cause or mechanism of this major oocyte loss remains an enigma. The oocyte goes through Meiotic Prophase I (MPI) in fetal life, when homologous chromosomes synapse and recombine. Proper homologous recombination is essential for correct chromosome segregation at meiotic divisions, which determines the success in embryonic development. It has been postulated that a surveillance mechanism operates to eliminate the oocytes with meiotic defects to promote the quality of oocytes in the ovarian reserve. We have previously shown that the oocyte population continuously declines throughout MPI progression, suggesting the presence of multiple causes for oocyte elimination[5].
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