Key Points
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Programmed cell death (apoptosis) claims up to 99.9% of the cells in the mammalian female germ line, which drives irreversible infertility, ovarian failure and the menopause in humans.
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Exciting insights into the mechanisms that underlie germ-cell apoptosis have recently been provided by the study of oocyte death in lower organisms and in genetically manipulated mice that lack apoptosis-regulatory proteins.
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Results from these investigations have already affected many aspects of biology and medicine - from advances in our understanding of mitochondrial inheritance and function in embryonic development to therapeutic approaches to preserve fertility and delay menopause. Furthermore, new cell death-signalling pathways have been uncovered from studies of female germ-cell death that have opened new research opportunities of broad scientific interest.
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However, many questions remained unanswered, and the reasons why the female body creates, only to delete, so many germ cells are still a mystery. This review summarizes what is known about the occurrence, regulation and functions of programmed cell death in the female germ line during embryonic and post-natal life, and how this information is being used for therapeutic purposes to try to combat infertility and the ageing process.
Abstract
Programmed cell death claims up to 99.9% of the cells in the mammalian female germ line, which eventually drives irreversible infertility and ovarian failure — the menopause in humans. New insights into the mechanisms that underlie germ-cell apoptosis have been provided by the study of oocyte death in lower organisms and in genetically manipulated mice that lack apoptosis-regulatory proteins. With new therapeutic tools to control fertility, oocyte quality and ovarian lifespan on the horizon, understanding how and why the female body creates, only to delete, so many germ cells is imperative.
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Acknowledgements
The author is indebted to the many past and current members of his laboratory, as well as to a number of colleagues and collaborators for their invaluable contributions, who collectively have made this review possible. The author also gratefully acknowledges the U.S. National Institutes of Health, the Department of Defense–U.S. Army Medical Research and Materiel Command's Office of Congressionally Directed Medical Research, the Steven and Michele Kirsch Foundation, and the Vincent Memorial Hospital Board of Trustees for their generous support of this work. The author apologizes for not citing other important contributions to the fields of programmed cell death and reproductive biology owing to space limitations.
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DATABASES
Glossary
- OOGENESIS
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The process of gamete formation in the female, which in mammals leads to the production of germ cells that are arrested in prophase-I of meiosis (oocytes) from a pool of mitotically active germ cells (oogonia).
- DIAKINESIS
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The point of the first meiotic block after the diploid germ cell in females (oogonium) progresses through the leptotene, zygotene and pachytene stages of prophase-I to become arrested in diplotene. In mammals, an oocyte reinitiates and completes meiosis-I after the preovulatory follicle that houses the oocyte receives the stimulus for ovulation.
- PRIMORDIAL FOLLICLES
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In vertebrates, each oocyte becomes enclosed by supportive somatic cells to form the most basic functional unit of the ovary, a follicle. The least differentiated type of follicle is referred to as primordial, being characterized by the presence of a single layer of squamous pre-granulosa somatic cells and its existence in a 'resting' state.
- MENOPAUSE
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A clinical diagnosis that is based on the permanent cessation of menses. In human females, the peri-menopausal period is usually heralded by infertility, near exhaustion of the oocyte reserve, a cessation of ovarian function and a loss of menstrual cyclicity. Only humans and nonhuman primates have menses, so other animal species cannot have a 'true' menopause.
- HORMONE REPLACEMENT THERAPY
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(HRT). A therapeutic preparation of oestrogens, usually combined with a small amount of progestins, that is prescribed to alleviate some of the physical and psychological manifestations of menopause which are believed to result from the loss of ovarian function.
- ASSISTED REPRODUCTIVE TECHNOLOGIES
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(ART). These are clinical procedures that are designed to help achieve pregnancy. Most of these procedures include the retrieval and fertilization of a woman's eggs outside the body (in vitro fertilization or IVF) followed by return of the embryos to the uterus (embryo transfer or ET) for implantation.
- HISTOMORPHOMETRY
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A process by which an ovary is removed, fixed, embedded in paraffin and serially sectioned. The sections are mounted in order on glass microscope slides and stained with a vital dye, such as haematoxylin–eosin. The total number of healthy versus dead/dying oocytes per section is then determined by light microscopic analysis.
- PER–ARNT–SIM (PAS) FAMILY
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A group of interacting and structurally related basic helix–loop–helix (bHLH) transcription factors.
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Tilly, J. Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol 2, 838–848 (2001). https://doi.org/10.1038/35099086
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DOI: https://doi.org/10.1038/35099086
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