TAp73 is downregulated in oocytes from women of advanced reproductive age

Guglielmino, Maria Rosa; Santonocito, Manuela; Vento, Marilena; Ragusa, Marco; Barbagallo, Davide; Borzì, Placido; Casciano, Ida; Banelli, Barbara; Barbieri, Ottavia; Astigiano, Simonetta; Scollo, Paolo; Romani, Massimo; Purrello, Francesco; Pietro, Cinzia Di

doi:10.4161/cc.10.19.17585

Cited by 42 publications

(28 citation statements)

References 35 publications

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“…aging, [27][28][29] and metabolism 27 through the regulation of gene [30][31][32] and microRNA expression. Mice deficient in p73 display neuronal pathologies, including hydrocephalus and hippocampal dysgenesis, with defects in the CA1-CA3 pyramidal cell layers and the dentate gyrus.…”

Section: Introductionmentioning

confidence: 99%

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Velletri

Romeo²,

Tucci

et al. 2013

Cell Cycle

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The amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). Two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53. Here, we show that the p53 family member TAp73 also drives the expression of GLS2. Specifically, we demonstrate that TAp73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells, and overexpression or inhibition of GLS2 modulates neuronal differentiation and intracellular levels of ATP. Moreover, inhibition of GLS activity, by removing Glutamine from the growth medium, impairs in vitro differentiation of cortical neurons. Finally, expression of GLS2 increases during mouse cerebellar development. Although, p73 is dispensable for the in vivo expression of GLS2, TAp73 loss affects GABA and Glutamate levels in cortical neurons. Together, these findings suggest a role for GLS2 acting, at least in part, downstream of p73 in neuronal differentiation and highlight a possible role of p73 in regulating neurotransmitter synthesis

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Section: Introductionmentioning

confidence: 99%

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Velletri

Romeo²,

Tucci

et al. 2013

Cell Cycle

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“…There is some evidence of an alteration in DNA methylation patterns within oocytes derived from older female animals (120), and there is one report of an alteration of DNA methylation patterns within metaphase II oocytes derived from women over 38 years of age compared with women under 35 years of age (133), and there are reports of a reduction in histone protein deacetylation in the metaphase I and II surplus oocytes derived from older women (355), and an alteration in the expression of ubiquilin in metaphase II oocytes (131). Hence, the consensus view is that oocytes derived from older women may be at risk of epigenetic modification (120).…”

Section: Oocyte Qualitymentioning

confidence: 99%

Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics

Hart

2016

Physiological Reviews

170

119

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Across the Western World there is an increasing trend to postpone childbearing. Consequently, the negative influence of age on oocyte quality may lead to a difficulty in conceiving for many couples. Furthermore, lifestyle factors may exacerbate a couple's difficulty in conceiving due mainly to the metabolic influence of obesity; however, the negative impacts of low peripheral body fat, excessive exercise, the increasing prevalence of sexually transmitted diseases, and smoking all have significant negative effects on fertility. Other factors that impede conception are the perceived increasing prevalence of the polycystic ovary syndrome, which is further exacerbated by obesity, and the presence of uterine fibroids and endometriosis (a progressive pelvic inflammatory disorder) which are more prevalent in older women. A tendency for an earlier sexual debut and to have more sexual partners has led to an increase in sexually transmitted diseases. In addition, there are several genetic influences that may limit the number of oocytes within the ovary; consequently, by postponing attempts at childbearing, a limitation of oocyte number may become evident, whereas in previous generations with earlier conception this potentially reduced reproductive life span did not manifest in infertility. Environmental influences on reproduction are under increasing scrutiny. Although firm evidence is lacking however, dioxin exposure may be linked to endometriosis, phthalate exposure may influence ovarian reserve, and bisphenol A may interfere with oocyte development and maturation. However, chemotherapy or radiotherapy is recognized to lead to ovarian damage and predispose the woman to ovarian failure.

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“…Approximately, 45-50 maternal-effect genes have been identified in mammals, and many of these are involved in chromatin structure, modification and genome integrity (Zhang and Smith, 2015). Reduced levels of maternal-effect genes have been associated with the reduced oocyte developmental competence that is characteristic of ovarian aging (Guglielmino et al, 2011;Hamatani et al, 2004;Pan et al, 2008;Zhang and Smith, 2015). The IVF experiments presented in this study show that embryogenesis is aberrant only when Smc5 is mutated during the oocyte growth phase, and provision of a functional Smc5 gene from sperm is insufficient to facilitate embryogenesis.…”

Section: Smc5 Is a Maternal-effect Genementioning

confidence: 99%

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

et al. 2017

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SMC complexes include three major classes: cohesin, condensin and SMC5/6. However, the localization pattern and genetic requirements for the SMC5/6 complex during mammalian oogenesis have not previously been examined. In mouse oocytes, the SMC5/6 complex is enriched at the pericentromeric heterochromatin, and also localizes along chromosome arms during meiosis. The infertility phenotypes of females with a Zp3-Cre-driven conditional knockout (cKO) of Smc5 demonstrated that maternally expressed SMC5 protein is essential for early embryogenesis. Interestingly, protein levels of SMC5/6 complex components in oocytes decline as wild-type females age. When SMC5/6 complexes were completely absent in oocytes during meiotic resumption, homologous chromosomes failed to segregate accurately during meiosis I. Despite what appears to be an inability to resolve concatenation between chromosomes during meiosis, localization of topoisomerase IIα to bivalents was not affected; however, localization of condensin along the chromosome axes was perturbed. Taken together, these data demonstrate that the SMC5/6 complex is essential for the formation of segregation-competent bivalents during meiosis I, and findings suggest that age-dependent depletion of the SMC5/6 complex in oocytes could contribute to increased incidence of oocyte aneuploidy and spontaneous abortion in aging females.

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TAp73 is downregulated in oocytes from women of advanced reproductive age

Cited by 42 publications

References 35 publications

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

Physiological Aspects of Female Fertility: Role of the Environment, Modern Lifestyle, and Genetics

SMC5/6 is required for the formation of segregation-competent bivalent chromosomes during meiosis I in mouse oocytes

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