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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

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Gene expression of mouse embryonic gonad [Nanos3]

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

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

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

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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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