TAp73 is required for spermatogenesis and the maintenance of male fertility

Inoue, Satoshi; Tomasini, Richard; Rufini, Alessandro; Elia, Andrew; Agostini, Massimiliano; Amelio, Ivano; Cescon, DW; Dinsdale, David; Zhou, Lily; Harris, Isaac S.; Lac, Sophie; Silvester, Jennifer; Li, Wanda Y.; Sato, Masato; Haight, Jillian; Brüstle, Anne; Wakeham, Andrew; McKerlie, Colin; Jurisicova, Andrea; Melino, Gerry; Mak, Tak W.

doi:10.1073/pnas.1323416111

Cited by 84 publications

(87 citation statements)

References 29 publications

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“…2 Full-length p73 regulates neuronal stem cell maintenance, metabolism, spermatogenesis, cell cycle arrest, and apoptosis, whereas recent evidence suggests that elevated expression of short p73 isoforms contributes to several types of cancer. 32,33 The current data support that differential expression of p53, p63, and p73 isoforms in different developing tissues and tumors have important functional consequences, but the understanding of these complex interactions is far from complete.…”

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confidence: 59%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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The p53 protein is a major mediator of the cellular response to genotoxic stress and is a crucial suppressor of tumor formation. In a variety of organisms, p53 and its paralogs, p63 and p73, each encode multiple protein isoforms through alternative splicing, promoters, and translation start sites. The function of these isoforms in development and disease are still being defined. Here, we evaluate the apoptotic potential of multiple isoforms of the single p53 gene in the genetic model Drosophila melanogaster. Most previous studies have focused on the p53A isoform, but it has been recently shown that a larger p53B isoform can induce apoptosis when overexpressed. It has remained unclear, however, whether one or both isoforms are required for the apoptotic response to genotoxic stress. We show that p53B is a much more potent inducer of apoptosis than p53A when overexpressed. Overexpression of two newly identified short isoforms perturbed development and inhibited the apoptotic response to ionizing radiation. Analysis of physiological protein expression indicated that p53A is the most abundant isoform, and that both p53A and p53B can form a complex and co-localize to sub-nuclear compartments. In contrast to the overexpression results, new isoformspecific loss-of-function mutants indicated that it is the shorter p53A isoform, not full-length p53B, that is the primary mediator of pro-apoptotic gene transcription and apoptosis after ionizing radiation. Together, our data show that it is the shorter p53A isoform that mediates the apoptotic response to DNA damage, and further suggest that p53B and shorter isoforms have specialized functions.

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confidence: 59%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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“…Consistent with this idea, we observed a reduction in SirT1 levels in the testes of aging male mice. Deletion of TAp73 (Inoue et al, 2014), GATA4 (Kyronlahti et al, 2011) and XPA (Nakane et al, 2008) results in an agedependent deterioration of seminiferous tubules, primarily due to defects in germ cell proliferation (TAp73), Sertoli cell and Leydig cell maturation and dysfunction (TAp73 and GATA4) and a lack of post-meiotic cells (TAp73, GATA4 and Xpa). Deletion of SirT1 results in accelerated reproductive aging without a loss of postmeiotic cells or defects in somatic cell abundance or function, indicating that SirT1 plays a unique role in the aging of the testes.…”

Section: Discussionmentioning

confidence: 99%

SirT1 is required in the male germ cell for differentiation and fecundity in mice

et al. 2014

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Sirtuins are NAD + -dependent deacylases that regulate numerous biological processes in response to the environment. SirT1 is the mammalian ortholog of yeast Sir2, and is involved in many metabolic pathways in somatic tissues. Whole body deletion of SirT1 alters reproductive function in oocytes and the testes, in part caused by defects in central neuro-endocrine control. To study the function of SirT1 specifically in the male germ line, we deleted this sirtuin in male germ cells and found that mutant mice had smaller testes, a delay in differentiation of pre-meiotic germ cells, decreased spermatozoa number, an increased proportion of abnormal spermatozoa and reduced fertility. At the molecular level, mutants do not have the characteristic increase in acetylation of histone H4 at residues K5, K8 and K12 during spermiogenesis and demonstrate corresponding defects in the histone to protamine transition. Our findings thus reveal a germ cell-autonomous role of SirT1 in spermatogenesis.

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“…Accordingly, over 70 % of the TAp73 selective knockout mice (TAp73−/−) show an increased susceptibility to both spontaneous and induced carcinogenesis [34]. In addition, TAp73−/− mice are infertile and exhibit hippocampal dysgenesis, indicating a role for the TAp73 isoform in the regulation of reproduction and in neuronal development [35][36][37][38].…”

Section: Introductionmentioning

confidence: 99%

How Does p73 Cause Neuronal Defects?

et al. 2015

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The p53-family member, p73, plays a key role in the development of the central nervous system (CNS), in senescence, and in tumor formation. The role of p73 in neuronal differentiation is complex and involves several downstream pathways. Indeed, in the last few years, we have learnt that TAp73 directly or indirectly regulates several genes involved in neural biology. In particular, TAp73 is involved in the maintenance of neural stem/progenitor cell self-renewal and differentiation throughout the regulation of SOX-2, Hey-2, TRIM32 and Notch. In addition, TAp73 is also implicated in the regulation of the differentiation and function of postmitotic neurons by regulating the expression of p75NTR and GLS2 (glutamine metabolism). Further still, the regulation of miR-34a by TAp73 indicates that microRNAs can also participate in this multifunctional role of p73 in adult brain physiology. However, contradictory results still exist in the relationship between p73 and brain disorders, and this remains an important area for further investigation.

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TAp73 is required for spermatogenesis and the maintenance of male fertility

Cited by 84 publications

References 29 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

SirT1 is required in the male germ cell for differentiation and fecundity in mice

How Does p73 Cause Neuronal Defects?

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