Dead end and Detour: The function of the RNA-binding protein Dnd in posttranscriptional regulation in the germline

Groß-Thebing, Theresa; Raz, Erez

doi:10.1016/bs.ctdb.2019.12.003

Cited by 12 publications

(10 citation statements)

References 105 publications

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“…differentiate towards other lineages and are not lost by apoptosis is supported by the observation that aggregate size and total cell numbers are increased in TS KO aggregates compared to the WT counterpart. This is in agreement with studies in zebrafish and mouse showing that DND is not needed for PGC specification, but is of upmost importance for maintenance and further development of the germline [1,4,6]. Our current results may also be explained by differentiation of iMeLCs to other cell types showing stronger mitotic expansion.…”

Section: Plos Onesupporting

confidence: 93%

“…The DND microRNA-mediated repression inhibitor 1 (DND1) is the human homolog of dead end (dnd), a conserved RNA binding protein (RBP) that plays an important role in survival and maintenance of primordial germ cells (PGCs) and the development of the male germline [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

“…The Ter mutation in murine DND1 -introducing a premature stop codon that disrupts RNA binding-is associated with male infertility and with a sharp increase in teratoma formation when introduced in mice of the 129/sv background [7]. This emphasizes its role in maintaining the germ cell fate and in regulating the latent pluripotency of PGCs [1,15].…”

Section: Introductionmentioning

confidence: 99%

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Heading towards a dead end: The role of DND1 in germ line differentiation of human iPSCs

et al. 2021

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The DND microRNA-mediated repression inhibitor 1 (DND1) is a conserved RNA binding protein (RBP) that plays important roles in survival and fate maintenance of primordial germ cells (PGCs) and in the development of the male germline in zebrafish and mice. Dead end was shown to be expressed in human pluripotent stem cells (PSCs), PGCs and spermatogonia, but little is known about its specific role concerning pluripotency and human germline development. Here we use CRISPR/Cas mediated knockout and PGC-like cell (PGCLC) differentiation in human iPSCs to determine if DND1 (1) plays a role in maintaining pluripotency and (2) in specification of PGCLCs. We generated several clonal lines carrying biallelic loss of function mutations and analysed their differentiation potential towards PGCLCs and their gene expression on RNA and protein levels via RNA sequencing and mass spectrometry. The generated knockout iPSCs showed no differences in pluripotency gene expression, proliferation, or trilineage differentiation potential, but yielded reduced numbers of PGCLCs as compared with their parental iPSCs. RNAseq analysis of mutated PGCLCs revealed that the overall gene expression remains like non-mutated PGCLCs. However, reduced expression of genes associated with PGC differentiation and maintenance (e.g., NANOS3, PRDM1) was observed. Together, we show that DND1 iPSCs maintain their pluripotency but exhibit a reduced differentiation to PGCLCs. This versatile model will allow further analysis of the specific mechanisms by which DND1 influences PGC differentiation and maintenance.

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Section: Plos Onesupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heading towards a dead end: The role of DND1 in germ line differentiation of human iPSCs

et al. 2021

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“…The fact that the soluble versus condensed states of these complexes are specifically required in distinct developmental and physiological contexts strongly suggests that the transition betwe en these states is subjected to tight cellular regulation (Banani et al, 2017; Boeynaems et al, 2018; Dodson & Kennedy, 2020; Folkmann et al, 2021; Hyman et al, 2014). For example, RNA binding proteins often contain IDRs adjacent to their RNA binding domains, such that initial RNA binding increases the IDR concentrations over the required threshold for their interactions to trigger phase separation (Folkmann et al, 2021; Gross-Thebing & Raz, 2020; Guo & Shorter, 2015; Luo et al, 2018). RNA binding in such cases can be regulated to control the rate and extent of phase separation of their corresponding RNP granule (Folkmann et al, 2021; Gross-Thebing & Raz, 2020; Guo & Shorter, 2015; Luo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…For example, RNA binding proteins often contain IDRs adjacent to their RNA binding domains, such that initial RNA binding increases the IDR concentrations over the required threshold for their interactions to trigger phase separation (Folkmann et al, 2021; Gross-Thebing & Raz, 2020; Guo & Shorter, 2015; Luo et al, 2018). RNA binding in such cases can be regulated to control the rate and extent of phase separation of their corresponding RNP granule (Folkmann et al, 2021; Gross-Thebing & Raz, 2020; Guo & Shorter, 2015; Luo et al, 2018). Recent work has revealed that RNA can also promote phase separation independently of IDRs (see chapter 1.1.1 .)…”

Section: Introductionmentioning

confidence: 99%

Multi-Step Cellular Control of Molecular Condensation by Microtubules in Early Oogenesis

Deis

Elkouby

2022

Preprint

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Molecular condensates provide new paradigms in biology, but their cellular regulation is unclear. Condensates undergo phase separation, decreasing their solubility and compartmentalizing their content. In vertebrate oocytes, RNA-protein (RNP) granules form condensates by phase separation, but the underlying mechanisms are unknown. RNP granules localize to the Balbiani body (Bb), a conserved membraneless organelle, that establishes oocyte polarity. Bb loss results in symmetrical eggs and embryonic lethality. Bb granules aggregate around the centrosome in a nuclear cleft, prior to assembling the mature structure. The Bucky ball (Buc) protein nucleates Bb granules and is essential for Bb formation. Howe ver, the dynamics, mechanisms, and regulation of Bb granule nucleation are unclear. While the mature Bb structure was shown to be a rigid, amyloid-like, phase-separated structure in Xenopus, the early phase separation dynamics prior to maturation are completely unknown. Here, by live, genetic, super-resolution microscopy, and FRAP analyses in zebrafish ovaries, we establish that Buc phase-separates Bb granules and that microtubules play multiple stepwise roles in controlling Buc phase separation and Bb formation specifically at the early nuclear cleft stages. We show that Buc first phase-separates into dynamic liquid droplet-like granules that fuse to form the main Bb aggregate. We demonstrate that early aggregated Buc exhibited dynamic turnover and that this turnover requires dynein-mediated trafficking of Buc on a transient lattice of microtubules that we identified. At later stages, microtubules encapsulated the Bb, indicating a structural role. Thus, microtubules organize multiple steps in Bb condensation. Moreover, in the mature Bb, Buc was stable and required for Bb amyloid formation, finalizing Bb condensation. We found for the first time by live imaging, ThT-positive presumptive amyloid b-sheets in the mature zebrafish Bb, that we re absent in buc-/- oocytes. Thus, providing the first genetic evidence for Buc dependent formation of presumptive amyloid fibrils in the Bb. Molecular condensation is often viewe d as a self-assembly process. Here, we propose a novel paradigm for the cellular control over condensation mechanisms by microtubules in development. The regulation of Bb assembly and disassembly in the context of phase separation allows studying these mechanisms in physiological conditions, advancing their understanding in neurodegenerative disease and female reproduction.

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Circular RNA circFCHO2(hsa_circ_0002490) promotes the proliferation of melanoma by directly binding to DND1

Yang,

Li,

Wei

et al. 2024

Cell Biol Toxicol

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Circular RNAs (circRNAs) have been documented to play crucial roles in the biology of various cancers. However, their investigation in melanoma is still at an early stage, particularly as a broader mechanism beyond acting as miRNA sponges needs to be explored. We report here that circFCHO2(hsa_circ_0002490), a circRNA encompassing exons 19 and 20 of the FCHO2 gene, exhibited a consistent overexpression in melanoma tissues. Furthermore, elevated circFCHO2 levels demonstrated a positive correlation with the malignant phenotype and poor prognosis among the 158 melanoma patients studied. Besides, we observed that heightened levels of circFCHO2 promoted melanoma cell proliferation, migration, and invasion in vitro, along with contributing to tumor growth in vivo. Furthermore, we found differences in the secondary structure of circFCHO2 compared to most other circular RNA structures. It has fewer miRNA binding sites, while it has more RNA binding protein binding sites. We therefore speculate that circFCHO2 may have a function of interacting with RNA binding proteins. Mechanistically, it was confirmed by fluorescence in situ hybridization (FISH), RNA-pull down, RNA immunoprecipitation (RIP), and western blotting assays that circFCHO2 interacts with dead end protein homolog 1 (DND1) and reverses the inhibition of the PI3K/AKT signaling pathway by binding to DND1. Our findings reveal that circFCHO2 drives melanoma progression by regulating the PI3K/AKT signaling pathway through direct binding to DND1 and may serve as a potential diagnostic biomarker and therapeutic target for the treatment of melanoma. Graphical Abstract Headlights: CircFCHO2 is highly expressed in melanoma. High circFCHO2 levels were positively correlated with poor prognosis in 158 melanoma patients. CircFCHO2 is involved in the regulation of the PI3K/AKT signalling pathway by binding to DND1. CircFCHO2 could serve as a potential biomarker and therapeutic target for the management of melanoma.

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Dead end and Detour: The function of the RNA-binding protein Dnd in posttranscriptional regulation in the germline

Cited by 12 publications

References 105 publications

Heading towards a dead end: The role of DND1 in germ line differentiation of human iPSCs

Heading towards a dead end: The role of DND1 in germ line differentiation of human iPSCs

Multi-Step Cellular Control of Molecular Condensation by Microtubules in Early Oogenesis

Circular RNA circFCHO2(hsa_circ_0002490) promotes the proliferation of melanoma by directly binding to DND1

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