TAp73 is essential for germ cell adhesion and maturation in testis

Holembowski, Lena; Krämer, Daniela; Riedel, Dietmar; Sordella, Raffaella; Nemajerová, Alice; Dobbelstein, Matthias; Moll, Ute M.

doi:10.1083/jcb.201306066

Cited by 47 publications

(61 citation statements)

References 47 publications

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“…For example, successful implantation of fertilized eggs in mice is regulated by p53 through the transactivation of leukemia inhibitory factor ( Lif ) [3]. On the other hand, p63 protects the female germline by eliminating damaged oocytes [4], whereas p73 is essential for sperm cell adhesion and maturation of testes [5]. Furthermore, p73 prevents abnormal chromosome segregation by regulating the spindle assembly checkpoint, which senses improper mitotic spindle attachments [6].…”

Section: Introductionmentioning

confidence: 99%

The p53-like Protein CEP-1 Is Required for Meiotic Fidelity in C. elegans

et al. 2016

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SUMMARY The passage of genetic information during meiosis requires exceptionally high fidelity to prevent birth defects and infertility. Accurate chromosome segregation during the first meiotic division relies on the formation of crossovers between homologous chromosomes and a series of precisely controlled steps to exchange genetic information. Many studies have hinted at a role for p53 in meiosis, but how it functions in this process is poorly understood. Here, we have identified a cooperative role for the p53-like protein CEP-1 and the meiotic protein HIM-5 in maintaining genome stability in the C. elegans germline. Loss of cep-1 and him-5 results in synthetic lethality that is dependent on the upstream DNA damage checkpoint but independent of the downstream core apoptotic pathway. We show that this synthetic lethality is the result of defective crossover formation due to reduced SPO-11-dependent double-strand breaks. Using cep-1 separation-of-function alleles, we show that cep-1 and him-5 also suppress inappropriate activation of the nonhomologous end joining (NHEJ) pathway. This work reveals an ancestral function for the p53 family in ensuring the fidelity of meiosis and establishes CEP-1 as a critical determinant of repair pathway choice.

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Section: Introductionmentioning

confidence: 99%

The p53-like Protein CEP-1 Is Required for Meiotic Fidelity in C. elegans

et al. 2016

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“…Female TAp73 knockout mice are infertile, reportedly from poor oocyte quality and ovarian egg release defects (Tomasini et al 2008). In testis, TAp73 regulates germ cell maturation, and male TAp73 knockouts are strongly subfertile (Holembowski et al 2014).…”

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confidence: 99%

TAp73 is a central transcriptional regulator of airway multiciliogenesis

Krämer²,

et al. 2016

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Motile multiciliated cells (MCCs) have critical roles in respiratory health and disease and are essential for cleaning inhaled pollutants and pathogens from airways. Despite their significance for human disease, the transcriptional control that governs multiciliogenesis remains poorly understood. Here we identify TP73, a p53 homolog, as governing the program for airway multiciliogenesis. Mice with TP73 deficiency suffer from chronic respiratory tract infections due to profound defects in ciliogenesis and complete loss of mucociliary clearance. Organotypic airway cultures pinpoint TAp73 as necessary and sufficient for basal body docking, axonemal extension, and motility during the differentiation of MCC progenitors. Mechanistically, cross-species genomic analyses and complete ciliary rescue of knockout MCCs identify TAp73 as the conserved central transcriptional integrator of multiciliogenesis. TAp73 directly activates the key regulators FoxJ1, Rfx2, Rfx3, and miR34bc plus nearly 50 structural and functional ciliary genes, some of which are associated with human ciliopathies. Our results position TAp73 as a novel central regulator of MCC differentiation.

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“…In vivo BTB assay was performed as described (Holembowski et al, 2014). Biotin labeled reagent (10 mg/ml Sulfo-NHS-SS-Biotin, Thermo Scientific) was freshly prepared in PBS containing 1 mM CaCl 2 , and then 25 µl of this solution were carefully injected into the center of the testis at low pressure.…”

Section: Methodsmentioning

confidence: 99%

“…Primary Sertoli cell culture was carried out as described (Sato et al, 2013; Holembowski et al, 2014) with some modifications. Briefly, to obtain Sertoli cells for primary culture, testes of adult mice were decapsulated in HBSS and seminiferous tubules were dispersed in a HBSS solution containing collagenase (0.1%)/hyaluronidase (0.1%)/DNase (0.04%) for 20 min at 34°C.…”

Section: Methodsmentioning

confidence: 99%

Functional importance of JMY expression by Sertoli cells in mediating mouse spermatogenesis

Fan

Yan

et al. 2018

Preprint

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3Sertoli cells are crucial for spermatogenesis in the seminiferous epithelium because 2 4 their actin cytoskeleton supports vesicle transport, cell junction, protein anchoring and 2 5 spermiation. Here, we show that junction-mediating and regulatory protein (JMY), an 2 6 actin regulating protein, also affects endocytic vesicle trafficking and Sertoli cell 2 7 junction remodeling since disruption of these functions induced male subfertility in 2 8Sertoli cell-specific Jmy knockout mice. Specifically, these mice have: a) impaired 2 9 BTB integrity and spermatid adhesion in the seminiferous tubules; b) high incidence 3 0 of sperm structural deformity; c) reduced sperm count and poor sperm motility. 3 1 Moreover, the cytoskeletal integrity in Sertoli cell-specific Jmy knockout mice was 3 2 compromised along with endocytic vesicular trafficking. These effects impaired 3 3 junctional protein recycling and reduced Sertoli cell junctions. In addition, JMY 3 4 interaction with α -actinin1 and Sorbs2 was related to JMY activity and in turn actin 3 5 cytoskeletal organization. In summary, JMY affects control of spermatogenesis 3 6 through regulating actin filament organization and endocytic vesicle trafficking in 3 7 Sertoli cells. 3 8 3 9

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TAp73 is essential for germ cell adhesion and maturation in testis

Abstract: The p53 family member TAp73 is required for sperm maturation through promotion of adhesion between developing germ cells and Sertoli nurse cells.

Cited by 47 publications

References 47 publications

The p53-like Protein CEP-1 Is Required for Meiotic Fidelity in C. elegans

The p53-like Protein CEP-1 Is Required for Meiotic Fidelity in C. elegans

TAp73 is a central transcriptional regulator of airway multiciliogenesis

Functional importance of JMY expression by Sertoli cells in mediating mouse spermatogenesis

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