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Truncated DAZL mutation reduces NANOS3 expression in primordial germ cells and leads to premature ovarian insufficiency

ABSTRACT: Primary ovarian insufficiency (POI) is a complex disorder that affects many genes and the underlying molecular mechanisms remain to be fully elucidated. In this study, a homozygous point mutation, c.808C>T, in the DAZL gene of a POI patient was identified. This homozygous variant causes a C-terminal truncation of DAZL and down-regulation of germ-line gene NANOS3 expression, among other dysregulated genes, in human primordial germ cells (hPGCs) in vitro. Mechanistically, we discovered that the truncated DAZL had defects in regulating mRNA translation for NANOS3, VASA, and SYCP3 - all essential for gametogenesis. Additionally, the truncated DAZL showed impaired interaction with Poly(A)-binding proteins (PABPs), a crucial component of the translation initiation complex. At the cellular level, the truncated mutation resulted in increased apoptosis of in vitro hPGCs. Our findings reveal that the c.808C>T mutation in DAZL causes dysregulated expressions of many genes, increases germ cell apoptosis and ultimately leads to POI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245155 | GEO | 2023/10/18

REPOSITORIES: GEO

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Truncated DAZL mutation reduces NANOS3 expression in primordial germ cells and leads to premature ovarian insufficiency

Project description:Truncated DAZL mutation reduces NANOS3 expression in primordial germ cells and leads to premature ovarian insufficiency

| PRJNA1027259 | ENA

DAZL regulates proliferation of human primordial germ cell by direct binding to precursor miRNAs and enhances DICER processing activity

Project description:Understanding the molecular and cellular mechanisms of human primordial germ cells (hPGCs) is essential in studying infertility and germ cell tumorigenesis. Many RNA binding proteins (RBPs) and non-coding RNAs are specifically expressed and functional during hPGC developments. However, the roles and regulatory mechanisms of these RBPs and non-coding RNAs, such as microRNAs (miRNAs), in hPGCs remain elusive. In this study, we reported a new regulatory function of DAZL, a germ cellspecific RBP, in miRNA biogenesis and cell proliferation. First, DAZL colocalized with miRNA let-7a in human PGCs and upregulated the levels of over a hundred mature miRNAs, including eight out of nine let-7 family, miR10, and miR199. Purified DAZL directly bound to the loops of precursor miRNAs with sequence specificity of GUU. The binding of DAZL to the precursor miRNA increased the maturation of miRNA by enhancing the cleavage activity of DICER. Furthermore, cell proliferation assay and cell cycle analysis confirmed that DAZL inhibited the proliferation of in vitro PGCs by promoting the maturation of these miRNAs. Evidently, the mature miRNAs upregulated by DAZL silenced cell proliferation regulators including TRIM71. Moreover, DAZL inhibited germline-tumor-cell proliferation and teratoma formation. These results demonstrate that DAZL regulates hPGC proliferation by enhancing miRNA processing.

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RNA-Seq of human embryonic stem cells over expressing NANOS3 and DAZL

Project description:Human embryonic stem cells (cell line HS401) were transfected with piggyBac over expression constructs for germ cell specific RNA binding proteins, Nanos homolog 3 (NANOS3) or Deleted in azoospermia-like (DAZL). Cells transfected with a construct without open reading frame (MOCK), were used as control. Biological triplicates from separate transfections were used for analysis. Total RNAs were ribodepleted and sequenced on one lane on an Illumina HiSeq2500 with a 2x101 setup in HighOutput mode.

2016-10-19 | E-MTAB-3849 | biostudies-arrayexpress

RNA-binding proteins DND1 and NANOS3 coordinately suppress SOX4 in processing bodies for restricting the entry of germ cell lineage

Project description:Specification of germ cell fate establishes the germline development during early embryogenesis, yet the underlying mechanisms remain largely unknown in humans. Here we focus on the functional roles of the RNA-binding protein (RBP) DND1 in human germline specification. We deleted the whole genomic region of DND1 in human embryonic stem cells (hESCs), based on which we generated human primordial germ cell-like cells (hPGCLCs). Interestingly, we discovered an increased percentage of hPGCLCs induced from DND1 deleted hESCs, suggesting that DND1 may restrict the specification of human germ cell lineage. Mechanistic investigation reveals that DND1 forms a complex with another RBP NANOS3, in which DND1 facilitates the binding of NANOS3 to their target mRNAs. Furthermore, by analyzing the mRNAs bound by DND1 and NANOS3, we identified SOX4 mRNAs as the key downstream factor for DND1 and NANOS3 complex to restrict the induction of hPGCLCs. Interestingly, DND1 and NANOS3 function in processing bodies (P-bodies) to repress the translation of SOX4 mRNAs, where NANOS3 bridges the interaction between DND1 and the translational repressor 4E-T. Altogether, these findings identify the RBPs DND1 and NANOS3 as “break system” to restrict the entry of germ cell fate in humans.

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scRNA-Seq of bovine fetal testes derived from NANOS3 knockout and wildtype embryos

Project description:We performed single cell RNA-sequencing (scRNA-Seq) of testes from bovine fetuses derived from either CRISPR/Cas9 NANOS3 knockout (KO; NANOS3 -/-) or wildtype control (NANOS3 +/+) embryos. The scRNA-Seq analysis showed a complete loss of primordial germ cells (PGCs) and gonocytes in NANOS3 KO fetal testes, while maintaining the development of somatic support cells.

2023-11-15 | GSE244321 | GEO

Gene expression of mouse embryonic gonad [Nanos3]

Project description:To identify germ cell- and somatic cell-specific gene expression profiles, we performed expression microarray analysis of the mouse gonads of the Nanos3+/-, Nanos3-/- female and male embryos from E12.5 to E15.5.

2013-02-06 | GSE38297 | GEO

Dazl regulates germ cell survival through a network of polA-proximal mRNA interactions [GC1-spg cells (parental line) iCLIP]

Project description:The RNA binding protein Dazl is essential for gametogenesis, but its direct in vivo functions, RNA targets, and the molecular basis for germ cell loss in DAZL null mice are unknown. Here, we mapped transcriptome-wide Dazl-RNA interactions in vivo, revealing Dazl binding to thousands of mRNAs via polyA-proximal 3’UTR interactions. In parallel, fluorescence activated cell sorting and RNA-Seq identified mRNAs sensitive to Dazl deletion in male germ cells. Despite binding a broad set of mRNAs, integrative analyses indicate that Dazl post-transcriptionally controls only a subset of its mRNA targets, namely those corresponding to a network of genes critical for germ cell proliferation and survival. Additionally, we provide evidence that polyA sequences have key roles in specifying Dazl-RNA interactions across the transcriptome. Altogether, our results reveal a mechanism for Dazl-RNA binding, and illustrate that Dazl functions as a master regulator of a post-transcriptional mRNA program essential for germ cell survival.

2018-09-18 | GSE120098 | GEO

Dazl regulates germ cell survival through a network of polA-proximal mRNA interactions [GC1-spg cells (parental line) Ribosome Profiling and RNA-seq]

Project description:The RNA binding protein Dazl is essential for gametogenesis, but its direct in vivo functions, RNA targets, and the molecular basis for germ cell loss in DAZL null mice are unknown. Here, we mapped transcriptome-wide Dazl-RNA interactions in vivo, revealing Dazl binding to thousands of mRNAs via polyA-proximal 3?UTR interactions. In parallel, fluorescence activated cell sorting and RNA-Seq identified mRNAs sensitive to Dazl deletion in male germ cells. Despite binding a broad set of mRNAs, integrative analyses indicate that Dazl post-transcriptionally controls only a subset of its mRNA targets, namely those corresponding to a network of genes critical for germ cell proliferation and survival. Additionally, we provide evidence that polyA sequences have key roles in specifying Dazl-RNA interactions across the transcriptome. Altogether, our results reveal a mechanism for Dazl-RNA binding, and illustrate that Dazl functions as a master regulator of a post-transcriptional mRNA program essential for germ cell survival.

2018-09-18 | GSE120097 | GEO

Gene expression of mouse embryonic gonad [Nanos3]

2013-02-06 | E-GEOD-38297 | biostudies-arrayexpress

An RNA-interacting protein network regulates pluripotency in mammalian primordial germ cells (Dazl knockdown)

Project description:Primordial germ cells (PGCs) are the embryonic precursors to egg and sperm. When removed from the embryonic gonad, PGCs can give rise to embryonic germ cell lines (EGs), pluripotent stem cells that display most of the characteristics of embryonic stem cells (ESCs) including the ability to form teratomas and to contribute to chimera formation. In mice, EG cells can be derived between E8.5 up to E12.5 of embryonic development, at which point the PGCs undergo sexual differentiation and in the male transition into unipotent gonocytes. Dazl, a germ cell-specific RNA-binding protein, is specifically expressed in developing PGCs and is required for proper germ cell development. Dazl knockout mice are infertile, but the molecular mechanisms underlying this phenotype are still unknown. Here we demonstrate that Dazl localizes in granular structures in mammalian PGCs but not in ESCs. We demonstrate Dazl plays a central role in a large mRNA/protein interactive network that includes members of Fragile-X family RNA-binding proteins. We demonstrate that Dazl and Fxr1 play a central role in these granules and directly regulate the translation of specific core pluripotency factors, including Sox2 and Suz12. Global gene expression changes following Dazl knockdown in in vitro primordial germ cells. In vitro primordial germ cells carrying control and Dazl knockdown shRNAs were generated from Oct4-GFP ES cells and isolated by FACS analysis. The global gene expression profiles were analyzed by Agilent Mouse Whole Genome 4X44K one-color microarrays.

2013-12-31 | E-GEOD-39535 | biostudies-arrayexpress

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