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Separase phosphosite mutation leads to genome instability and primordial germ cell depletion during oogenesis.

ABSTRACT: To ensure equal chromosome segregation and the stability of the genome during cell division, Separase is strictly regulated primarily by Securin binding and inhibitory phosphorylation. By generating a mouse model that contained a mutation to the inhibitory phosphosite of Separase, we demonstrated that mice of both sexes are infertile. We showed that Separase deregulation leads to chromosome mis-segregation, genome instability, and eventually apoptosis of primordial germ cells (PGCs) during embryonic oogenesis. Although the PGCs of mutant male mice were completely depleted, a population of PGCs from mutant females survived Separase deregulation. The surviving PGCs completed oogenesis but produced deficient initial follicles. These results indicate a sexual dimorphism effect on PGCs from Separase deregulation, which may be correlated with a gender-specific discrepancy of Securin. Our results reveal that Separase phospho-regulation is critical for genome stability in oogenesis. Furthermore, we provided the first evidence of a pre-zygotic mitotic chromosome segregation error resulting from Separase deregulation, whose sex-specific differences may be a reason for the sexual dimorphism of aneuploidy in gametogenesis.

SUBMITTER: Xu J

PROVIDER: S-EPMC3073988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Deadenylase depletion protects inherited mRNAs in primordial germ cells.

Project description:A crucial event in animal development is the specification of primordial germ cells (PGCs), which become the stem cells that create sperm and eggs. How PGCs are created provides a valuable paradigm for understanding stem cells in general. We find that the PGCs of the sea urchin Strongylocentrotus purpuratus exhibit broad transcriptional repression, yet enrichment for a set of inherited mRNAs. Enrichment of several germline determinants in the PGCs requires the RNA-binding protein Nanos to target the transcript that encodes CNOT6, a deadenylase, for degradation in the PGCs, thereby creating a stable environment for RNA. Misexpression of CNOT6 in the PGCs results in their failure to retain Seawi transcripts and Vasa protein. Conversely, broad knockdown of CNOT6 expands the domain of Seawi RNA as well as exogenous reporters. Thus, Nanos-dependent spatially restricted CNOT6 differential expression is used to selectively localize germline RNAs to the PGCs. Our findings support a 'time capsule' model of germline determination, whereby the PGCs are insulated from differentiation by retaining the molecular characteristics of the totipotent egg and early embryo.

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Early depletion of primordial germ cells in zebrafish promotes testis formation.

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Early Depletion of Primordial Germ Cells in Zebrafish Promotes Testis Formation.

Project description: Not available

| S-EPMC4618446 | biostudies-literature

Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles.

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| S-EPMC3666718 | biostudies-literature

Complete depletion of primordial germ cells in an All-female fish leads to Sex-biased gene expression alteration and sterile All-male occurrence.

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| S-EPMC4652418 | biostudies-literature

Dynactin1 depletion leads to neuromuscular synapse instability and functional abnormalities.

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| S-EPMC6617949 | biostudies-literature

DPPA3 facilitates genome-wide DNA demethylation in mouse primordial germ cells.

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

Project description: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.

2023-10-18 | GSE245155 | GEO

SPOP mutation leads to genomic instability in prostate cancer.

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