Switch from BAX-dependent to BAX-independent germ cell loss during the development of fetal mouse ovaries

Alton, Michelle; Taketo, Teruko

doi:10.1242/jcs.03332

Cited by 36 publications

(37 citation statements)

References 51 publications

(54 reference statements)

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“…Although the absence of BMF resulted in elevated germ cell numbers at E15.5 and PN1, the numbers of primordial follicles established in the initial ovarian reserve were unchanged due to accelerated germ cell loss after PN1. These observations are reminiscent of those reported for Bax −/− mice (Alton & Taketo 2007). Approximately 1.5 times more GCNA1-positive germ cells were observed at E14.5 and E18.5 in ovaries from Bax −/− mice compared with ovaries from WT mice, suggesting that BAx plays an important role in the elimination of germ cells during the early stages of meiotic prophase (Alton & Taketo 2007).…”

Section: Discussionsupporting

confidence: 80%

“…We have recently shown that PUMA mediates germ cell death in mice before E13.5 (during the migratory and/or proliferative phase) and loss of PUMA results in approximately two-fold increase in primordial follicle number at birth (Myers et al 2014). Additionally, there has been much attention focussed on the role of the pro-apoptotic protein BAx in germ cell death (Rucker et al 2000, Stallock et al 2003, Alton & Taketo 2007, Greenfeld et al 2007a,b, Perez et al 2007, Ke et al 2013. Even though many of these studies have produced conflicting results regarding the requirement for BAx in the elimination of germ cells during different stages of ovarian development, there is consensus within the field that BAx is an important regulator of female germ cell death.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 80%

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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“…Similarly, deletion of the anti-apoptotic protein BCL2 was also found to reduce follicle endowment (Ratts et al 1995), whereas the overexpression of BCL2 was found to increase initial follicle number by 1.7-fold, though the number of primordial follicles did not remain elevated in adult life (Flaws et al 2001(Flaws et al , 2006. Finally, deletion of the pro-apoptotic multi-BH domain protein BAX was found to result in increased germ cell survival during embryonic development, with studies indicating that BAX mediates germ cell death prior to E13.5, similar to our findings for BBC3 (Alton & Taketo 2007, Greenfeld et al 2007. Furthermore, deletion of Bax was found to result in a 1.4-fold increase in the number of primordial follicles at birth (Greenfeld et al 2007), and another study indicated that the loss of Bax resulted in an elevated number of follicles throughout reproductive life, possibly due to reduced follicular atresia (Perez et al 1999).…”

Section: Discussionsupporting

confidence: 86%

PUMA regulates germ cell loss and primordial follicle endowment in mice

Myers¹,

Morgan²,

Liew³

et al. 2014

Reproduction

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The number of primordial follicles initially established within the ovary is influenced by the extent of germ cell death during foetal ovarian development, but the mechanisms that mediate this death have not been fully uncovered. In this study, we identified BBC3 (PUMA) (p53 upregulated modulator of apoptosis, also known as BCL2-binding component 3), a pro-apoptotic BH3-only protein belonging to the BCL2 family, as a critical determinant of the number of germ cells during ovarian development. Targeted disruption of the Bbc3 gene revealed a significant increase in the number of germ cells as early as embryonic day 13.5. The number of germ cells remained elevated in Bbc3 K/K female mice compared with WT female mice throughout the remainder of embryonic and early postnatal life, resulting in a 1.9-fold increase in the number of primordial follicles in the ovary on postnatal day 10. The increase in the number of germ cells observed in the ovaries of Bbc3 K/K mice could not be attributed to the altered proliferative activity of germ cells within the ovaries. Furthermore, BBC3 was found to be not required for the massive germ cell loss that occurs during germ cell nest breakdown. Our data indicate that BBC3 is a critical regulator of germ cell death that acts during the migratory phase of oogenesis or very soon after the arrival of germ cells in the gonad and that BBC3-mediated cell death limits the number of primordial follicles established in the initial ovarian reserve.

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“…27 For example, rhabdomyosarcoma malignant tumours are particularly sensitive to Bax invalidation, while ovarian germ cells, depending on their maturity degree, shift from Bax-dependent to Baxindependent apoptosis. 28,29 In the present study, we have found that siRNA-induced Bax suppression promotes survival of granule cell precursors. Concurrently, the activity of a transiently activated executioner caspase-3 was also blocked by Bax repression.…”

Section: Discussionsupporting

confidence: 56%

Bax siRNA promotes survival of cultured and allografted granule cell precursors through blockade of caspase-3 cleavage

et al. 2008

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Transplantation of neuronal precursor cells (NPCs) into the central nervous system could represent a powerful therapeutical tool against neurodegenerative diseases. Unfortunately, numerous NPCs die shortly after transplantation, predominantly due to caspase-dependent apoptosis. Using a culture of cerebellar neuronal precursors, we have previously demonstrated protective effect of the neuropeptide PACAP, which suppresses ceramide-induced apoptosis by blockade of the mitochondrial apoptotic pathway. The main objective of this study was to determine whether Bax repression can promote survival of NPCs allotransplanted into a host animal. In vivo and ex vivo experiments revealed that C2-ceramide increases Bax expression, while PACAP reverses this effect. In vitro tests using cerebellar NPCs demonstrated that the Bax-specific small interfering RNA (siRNA) could reduce their death and caspase-3 cleavage within the first 24 h. BrdU-labelled NPCs were subjected to transfection procedure with or without siRNA introduction before using for in vivo transplantation. Twenty-four hours after, the allografted NPCs containing siRNA showed significantly reduced level of caspase-3 cleavage, and the volume of their implants was almost twofold higher than in the case of empty-transfected precursors. These data evidence an important role of Bax in life/death decision of grafted NPCs and suggest that RNA interference strategy may be applicable for maintaining NPCs survival within the critical first hours after their transplantation.

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Switch from BAX-dependent to BAX-independent germ cell loss during the development of fetal mouse ovaries

Cited by 36 publications

References 51 publications

BCL2-modifying factor promotes germ cell loss during murine oogenesis

BCL2-modifying factor promotes germ cell loss during murine oogenesis

PUMA regulates germ cell loss and primordial follicle endowment in mice

Bax siRNA promotes survival of cultured and allografted granule cell precursors through blockade of caspase-3 cleavage

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