PUMA regulates germ cell loss and primordial follicle endowment in mice

Myers, Michelle; Morgan, Francis J.; Liew, Seng H.; Zerafa, Nadeen; Gamage, Thilini; Sarraj, Mai; Cook, Michele; Kapic, Ileana; Sutherland, Ann M.; Scott, Clare L.; Strasser, Andreas; Findlay, Jock K.; Kerr, J. B.; Hutt, Karla J.

doi:10.1530/rep-13-0666

Cited by 51 publications

(52 citation statements)

References 41 publications

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“…PUMA has also been implicated in the developmentally regulated germ cell loss that occurs during the embryonic migration of germ cells to the gonad and in the newly forming ovary (Myers et al 2014). Interestingly, mice genetically deficient in PUMA are endowed with an almost twofold increase in the normal number of primordial follicles, highlighting the key role PUMAmediated apoptosis plays in determining how many primordial follicles are initially established in the ovarian reserve (Myers et al 2014).…”

Section: Puma and Noxamentioning

confidence: 99%

“…Interestingly, mice genetically deficient in PUMA are endowed with an almost twofold increase in the normal number of primordial follicles, highlighting the key role PUMAmediated apoptosis plays in determining how many primordial follicles are initially established in the ovarian reserve (Myers et al 2014). However, it is not yet clear whether PUMA directly mediates germ cell apoptosis during this time, or whether PUMA initiates somatic cell apoptosis, which subsequently limits germ cell survival.…”

Section: Puma and Noxamentioning

confidence: 99%

“…Programmed cell death, or apoptosis morphology (hereafter referred to as 'apoptosis'), is a major feature of normal ovarian development, with more than twothirds of the germ cells produced during female embryonic development undergoing cell death shortly after they are formed (Pepling & Spradling 2001, Myers et al 2014. The apoptotic elimination of germ cells ultimately results in a reduced number of oocytes stored as primordial follicles within the ovary at birth (Myers et al 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The apoptotic elimination of germ cells ultimately results in a reduced number of oocytes stored as primordial follicles within the ovary at birth (Myers et al 2014). Once formed, primordial follicles may be lost from the ovarian reserve as a consequence of exposure to endogenous and exogenous stressors, such as chemotherapy, radiation and environmental toxicants (Kerr et al 2012a, Sobinoff et al 2013, Sivakumar et al 2014.…”

Section: Introductionmentioning

confidence: 99%

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The role of BH3-only proteins in apoptosis within the ovary

Hutt¹

2015

Reproduction

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BH3-only proteins are pro-apoptotic members of the BCL2 family that play pivotal roles in embryonic development, tissue homeostasis and immunity by triggering cell death through the intrinsic apoptosis pathway. Recent in vitro and in vivo studies have demonstrated that BH3-only proteins are also essential mediators of apoptosis within the ovary and are responsible for the initiation of the cell death signalling cascade in a cell type and stimulus-specific fashion. This review gives a brief overview of the intrinsic apoptosis pathway and summarise the roles of individual BH3-only proteins in the promotion of apoptosis in embryonic germ cells, oocytes, follicular granulosa cells and luteal cells. The role of these proteins in activating apoptosis in response to developmental cues and cell stressors, such as exposure to chemotherapy, radiation and environmental toxicants, is described. Studies on the function of BH3-only proteins in the ovary are providing valuable insights into the regulation of oocyte number and quality, as well as ovarian endocrine function, which collectively influence the female reproductive lifespan and health.Reproduction (2015) 149 R81-R89

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Section: Puma and Noxamentioning

confidence: 99%

Section: Puma and Noxamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of BH3-only proteins in apoptosis within the ovary

Hutt¹

2015

Reproduction

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“…Several studies suggest that germ cell death is mediated by the intrinsic (also known as the 'mitochondrial', 'BCL2-regulated' or 'stress-induced') apoptosis pathway (Ratts et al 1995, Felici et al 1999, Rucker et al 2000, Greenfeld et al 2007a, Ene et al 2013, Myers et al 2014. The intrinsic apoptosis pathway is regulated by the relative levels and activities of pro-and anti-apoptotic members of the BCL2 protein family (Youle & Strasser 2008, Czabotar et al 2014.…”

Section: Introductionmentioning

confidence: 99%

BCL2-modifying factor promotes germ cell loss during murine oogenesis

Vaithiyanathan¹,

Liew²,

Zerafa³

et al. 2016

Reproduction

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Apoptosis plays a prominent role during ovarian development by eliminating large numbers of germ cells from the female germ line. However, the precise mechanisms and regulatory proteins involved in germ cell death are yet to be determined. In this study, we characterised the role of the pro-apoptotic BH3-only protein, BCL2-modifying factor (BMF), in germ cell apoptosis in embryonic and neonatal mouse ovaries. BMF protein was immunohistochemically localised to germ cells at embryonic days 15.5 (E15.5) and E17.5 and postnatal day 1 (PN1), coincident with entry into the meiotic prophase, but was undetectable at E13.5, and only present at low levels at PN3 and PN5. Consistent with this expression pattern, loss of BMF in female mice was associated with a decrease in apoptosis at E15.5 and E17.5. Furthermore, increased numbers of germ cells were found in ovaries from Bmf −/− mice compared with WT animals at E15.5 and PN1. However, germ cell numbers were comparable between Bmf −/− and WT ovaries at PN3, PN5 and PN10. Collectively, these data indicate that BMF mediates foetal oocyte loss and its action limits the maximal number of germ cells attained in the developing ovary, but does not influence the number of primordial follicles initially established in ovarian reserve.

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Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

Grive

2020

Molecular Reproduction Devel

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The mammalian ovarian reserve is comprised of a finite pool of primordial follicles, representing the lifetime reproductive capacity of females. In most mammals, the reserve is produced during embryonic and early postnatal development with oocyte numbers peaking during mid‐to‐late gestation, and then experiencing a dramatic decline continuing until shortly after birth. Oocytes remaining after the bulk of this attrition are subsequently surrounded by a layer of somatic pre‐granulosa cells with these units then referred to as “primordial follicles.” The complex and varied cell death mechanisms intrinsic to this process are not only characteristic of, but also essential for, the proper formation of this pool of follicles, and as a result must be immaculately balanced to ensure long‐term fertility and reproductive health. Too few follicles can lead to Primary Ovarian Insufficiency, resulting in fertility loss and other features of aging, such as an overall shorter lifespan. On the other hand, whereas an excess of follicles might extend reproductive lifespan, this might also be the underlying etiology of other ovarian pathologies. The last decade, in particular, has vastly expanded our understanding of oocyte attrition and determinants of ovarian reserve abundance. By continuing to decipher the intricacies underlying the cell death processes and development of the initial primordial follicle pool, we may be in a much better position to understand idiopathic cases of premature follicle depletion and improve ovarian health in reproductive‐age women.

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PUMA regulates germ cell loss and primordial follicle endowment in mice

Cited by 51 publications

References 41 publications

The role of BH3-only proteins in apoptosis within the ovary

The role of BH3-only proteins in apoptosis within the ovary

BCL2-modifying factor promotes germ cell loss during murine oogenesis

Pathways coordinating oocyte attrition and abundance during mammalian ovarian reserve establishment

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