Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice

Yang, Qi-En; Nagaoka, So I.; Gwost, Ivy; Hunt, Patricia A.; Oatley, Jon M.

doi:10.1371/journal.pgen.1005355

Cited by 20 publications

(14 citation statements)

References 47 publications

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“…A deficiency of Retinoblastoma 1 (Rb1) or Forkhead box O3a (Foxo3a) has been shown to cause oocyte abnormality and ovarian teratoma. Although the mechanisms behind these remain unclear, the dysregulation of follicle growth due to Rb1 deficiency and impaired Foxo3a-directed apoptosis are likely associated with teratoma formation ( Yang et al, 2015 ; Youngson et al, 2011 ). In addition, the LT/Sv mouse strain exhibits a high frequency of spontaneous ovarian teratoma ( Eppig et al, 1996 ).…”

Section: Introductionmentioning

confidence: 99%

Dnd1-mediated epigenetic control of teratoma formation in mouse

Mochizuki

Otsuka

et al. 2018

Biology Open

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Spontaneous testicular teratoma develops from primordial germ cells (PGCs) in embryos; however, the molecular mechanisms underlying teratoma formation are not fully understood. Mutation of the dead-end 1 (Dnd1) gene, which encodes an RNA-binding protein, drastically enhances teratoma formation in the 129/Sv mouse strain. To elucidate the mechanism of Dnd1 mutation-induced teratoma formation, we focused on histone H3 lysine 27 (H3K27) trimethylation (me3), and found that the levels of H3K27me3 and its responsible methyltransferase, enhancer of zeste homolog 2 (Ezh2), were decreased in the teratoma-forming cells of Dnd1 mutant embryos. We also showed that Dnd1 suppressed miR-26a-mediated inhibition of Ezh2 expression, and that Dnd1 deficiency resulted in decreased H3K27me3 of a cell-cycle regulator gene, Ccnd1. In addition, Ezh2 expression or Ccnd1 deficiency repressed the reprogramming of PGCs into pluripotent stem cells, which mimicked the conversion of embryonic germ cells into teratoma-forming cells. These results revealed an epigenetic molecular linkage between Dnd1 and the suppression of testicular teratoma formation.

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Section: Introductionmentioning

confidence: 99%

Dnd1-mediated epigenetic control of teratoma formation in mouse

Mochizuki

Otsuka

et al. 2018

Biology Open

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“…The hypothesis of a pRB involvement in ovarian germ cell tumors predisposition is supported by the finding that RB1 conditional knockout in ovarian germ cells lead to the development of unilateral ovarian teratoma in mice (35,36). Interestingly, all the mice screened in the study by Yang et al developed only unilateral teratoma, so preneoplastic lesions, implicating that besides Rb inactivation, other genes or regulatory elements must be involved to promote tumor initiation.…”

Section: Discussionmentioning

confidence: 97%

RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report

et al. 2020

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Malignant ovarian germ cell tumors (MOGCTs) are neoplasms of the ovary, of which, due to their rarity and heterogeneity, few is reported about genetic background and development. Here, we report a 18-years old patient diagnosed with an ovarian mixed germ cell tumor, without any previous history of malignancies, who has been treated with surgery and chemotherapy and died 4 years later due to peritoneal metastasis complications. Patient's blood DNA was screened for a panel of 52 cancer-related genes in order to identify predisposing aberrations to this rare cancer. The analysis discovered the uncharacterized c.2393G>A variant in RB1, the retinoblastoma gene, leading both to a missense change and a splicing perturbation of the RB1 transcript. The variant was found to be hypomorphic, damaging the C-terminal domain with a partially impaired protein function. The variant is inherited from the unaffected mother. Due to an imprinting mechanism, the maternal allele is ∼3-fold more expressed than the paternal one. The parent-of-origin effect combined with the hypomorphic impact of the variant determines a rescue of sufficient tumor-suppressor activity to prevent retinoblastoma development but can predispose to other cancers in the adult age. In order to understand the somatic events acting on the germline predisposition we used the NGS-liquid biopsy covering 77 cancer driver genes. Using this approach, we detected deleterious mutations in TP53, SMAD4, FGFR3, and MSH2, indicative of a dis-regulation of cell cycle and DNA repair mechanisms pathways. In conclusion, we have pinpointed for the first time that an RB1 leaky variant, not leading to retinoblastoma because of its maternal origin, can predispose in adults to a very rare form of ovarian cancer and that the somatic disruption of few genes contributes to the tumor progression and aggressiveness.

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“…Deregulation of both RBR and MYB64/119 in Arabidopsis leads to super-numerary cells in the female gametophytes that are partially defective in establishing respective cell identities, which is reminiscent of cancer-like cell proliferation and oxidative cellular stress response. Female germline-specific requirement of RBR and MYBs in Arabidopsis and corresponding roles of their paralogues in mice oocytes [38, 45] illustrate how these dual modules might have retained their common reproductive function in evolution.…”

Section: Discussionmentioning

confidence: 99%

A RETINOBLASTOMA-RELATED transcription factor network governs egg cell differentiation and stress response inArabidopsis

Kirioukhova-Johnston

Pawar

Govind

et al. 2019

Preprint

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35The multicellular embryo, and ultimately the entire organism, is a derivative of the fertilized 36 egg cell. Unlike in animals, transcription factor networks orchestrating faithful egg 37 development are still largely unknown in plants. We have identified that egg cell 38 differentiation in Arabidopsis require interplay between evolutionarily conserved onco-protein 39 homologs RETINOBLASTOMA-RELATED (RBR) and redundant MYB proteins 40 MYB64/MYB119. RBR physically interacts with the MYBs; and with plant-specific 41 transcription factors belonging to the RWP-RK-domain (RKD) family and LEAFY 42 COTYLEDON1 (LEC1), which participate in development of egg cells and inherent stress 43 response. RBR binds to most of these egg cell-expressed loci at the DNA level, partially 44 overlapping with sites of histone methylation H3K27me3. Since deregulation of RKDs 45 phenocopies mutants of RBR and the MYBs in terms of cell proliferation in the egg cell 46 spatial domain, all the corresponding proteins are likely required to restrict parthenogenetic 47 cell divisions of the egg cells. Cross-talk among these transcription factors, and direct 48 regulation by RBR, govern egg cell development and expression of egg-to-zygotic polarity 49 factors of the WUSCHEL RELATED HOMEOBOX family. Together, a network of RBR-50 centric transcription factors underlies egg cell development and stress response, possibly, in 51 combination with several other predicted nodes. 52 53 54 55 Key words 56 egg cell | transcription factor | RETINOBLASTOMA RELATED | MYB | RKD | stress | 57 parthenogenesis 58 59 4 Author summary 60 61The RETINOBLASTOMA protein is one of the core components of the Eukaryotic 62 cell cycle, and corresponding evolutionary homologs have been implicated not only 63 to repress cell division but also to control differentiation and development. How 64 RETINOBLASTOMA RELATED (RBR) associate with other higher order regulators 65 to control faithful egg cell development in sexual plants is pivotal for manipulation of 66 successful reproduction in general, and engineering of parthenogenesis when 67 asexual or apomictic seed progeny are desirable over sexual plants. Using a suite of 68 molecular methods, we show that a RBR-associated transcription factor network 69 operates to specify egg cells in Arabidopsis. Complex cross-regulation within these 70 transcription factors seems to be necessary for successful maternal egg cell to 71 zygotic transition and reproductive stress response. Detailed genetic analysis 72 implicate that RBR and its interactive partners belonging to MYB and RWP-RK 73 transcription factor families are possibly required to prevent parthenogenesis of the 74 sexual egg cells. Novel RBR networks and stress nodes explained in this study 75 might help to improve our understanding of sexual and asexual reproduction. 76 77 78 79 80 Proper differentiation of the egg cells is pivotal for sexual reproduction as well as 81 parthenogenesis. In flowering plants, the egg cells are terminally differentiated within 82 the miniature ...

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Inactivation of Retinoblastoma Protein (Rb1) in the Oocyte: Evidence That Dysregulated Follicle Growth Drives Ovarian Teratoma Formation in Mice

Cited by 20 publications

References 47 publications

Dnd1-mediated epigenetic control of teratoma formation in mouse

Dnd1-mediated epigenetic control of teratoma formation in mouse

RB1 Germline Variant Predisposing to a Rare Ovarian Germ Cell Tumor: A Case Report

A RETINOBLASTOMA-RELATED transcription factor network governs egg cell differentiation and stress response inArabidopsis

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