Germ cell tumors: Insights from the <i>Drosophila</i> ovary and the mouse testis

Salz, Helen K.; Dawson, Emily P.; Heaney, Jason D.

doi:10.1002/mrd.22779

Cited by 16 publications

(11 citation statements)

References 136 publications

(159 reference statements)

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“…Specified primordial germ cells then migrate into the embryonic gonad, where they begin to exhibit sex-specific division rates and gene expression programs, ultimately leading to meiosis and differentiation into either eggs or sperm. Defects in sex-specific programming interferes with germ cell differentiation leading to infertility and germ cell tumors 1 , 2 . Successful reproduction, therefore, depends on the capacity of germ cells to maintain their sexual identity in the form of sex-specific regulation of gene expression.…”

Section: Introductionmentioning

confidence: 99%

The H3K9 methyltransferase SETDB1 maintains female identity in Drosophila germ cells

2018

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The preservation of germ cell sexual identity is essential for gametogenesis. Here we show that H3K9me3-mediated gene silencing is integral to female fate maintenance in Drosophila germ cells. Germ cell specific loss of the H3K9me3 pathway members, the H3K9 methyltransferase SETDB1, WDE, and HP1a, leads to ectopic expression of genes, many of which are normally expressed in testis. SETDB1 controls the accumulation of H3K9me3 over a subset of these genes without spreading into neighboring loci. At phf7, a regulator of male germ cell sexual fate, the H3K9me3 peak falls over the silenced testis-specific transcription start site. Furthermore, H3K9me3 recruitment to phf7 and repression of testis-specific transcription is dependent on the female sex determination gene Sxl. Thus, female identity is secured by an H3K9me3 epigenetic pathway in which Sxl is the upstream female-specific regulator, SETDB1 is the required chromatin writer, and phf7 is one of the critical SETDB1 target genes.

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Section: Introductionmentioning

confidence: 99%

The H3K9 methyltransferase SETDB1 maintains female identity in Drosophila germ cells

2018

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“…To specifically explore CENP-C function in GSC maintenance, we assayed the GSC/CB balance in CENP-C depleted germaria. To measure GSC/CB balance, we used the stem cell marker pMad [39] and SEX-LETHAL (SXL) that labels the GSC-CB transition up to the 2-cell cyst (2cc) stage [40,41] (Fig 6A-F and Fig S5A, S5B). Firstly, in control OregonR ( wild-type ) and RNAi isogenic control lines, we counted the number of pMad-positive and SXL-positive cells in each germaria at 5-days (Fig S5C).…”

Section: Resultsmentioning

confidence: 99%

CENP-C regulates centromere assembly, asymmetry and epigenetic age in Drosophila germline stem cells

Carty

Dattoli

Dunleavy

2020

Preprint

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Germline stem cells divide asymmetrically to produce one new daughter stem cell and one daughter cell that will subsequently undergo meiosis and differentiate to generate the mature gamete. The silent sister hypothesis proposes that in asymmetric divisions, the selective inheritance of sister chromatids carrying specific epigenetic marks between stem and daughter cells impacts cell fate. To facilitate this selective inheritance, the hypothesis specifically proposes that the centromeric region of each sister chromatid is distinct. In Drosophila germ line stem cells (GSCs), it has recently been shown that the centromeric histone CENP-A (called CID in flies) - the epigenetic determinant of centromere identity - is asymmetrically distributed between sister chromatids. In these cells, CID deposition occurs in G2 phase such that sister chromatids destined to end up in the stem cell harbour more CENP-A, assemble more kinetochore proteins and capture more spindle microtubules. These results suggest a potential mechanism of mitotic drive that might bias chromosome segregation. Here we report that the inner kinetochore protein CENP-C, is required for the assembly of CID in G2 phase in GSCs. Moreover, CENP-C is required to maintain a normal asymmetric distribution of CID between stem and daughter cells. In addition, we find that CID is lost from centromeres in aged GSCs and that a reduction in CENP-C accelerates this loss. Finally, we show that CENP-C depletion in GSCs disrupts the balance of stem and daughter cells in the ovary, shifting GSCs toward a self-renewal tendency. Ultimately, we provide evidence that centromere assembly and maintenance via CENP-C is required to sustain asymmetric divisions in female Drosophila GSCs.

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“…This includes the prone strain of mice (129J) that has been explained based on a dnd inactivating mutation [8]. Of interest is that a pleiotropy of genes disrupted in the embryonic germ cell lineage result in Type I-like teratomas (prepubertal type), including p53 , pten , and ras [9,10], while formation of yolk sac tumor has been only reported rarely [11]. The likely spontaneous animal model for the other variant of non-GCNIS-related GCT (spermatocytic tumor; Type III testicular GCTs) is the dog [12], while also a genetically modified mouse model has been described, although being presented as mimicking seminoma (i.e., Type II) [13,14].…”

Section: Spontaneous and Laboratory-generated Gct Animal Modelsmentioning

confidence: 99%

Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology

Looijenga

Kao

Idrees

2019

IJMS

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The risk of gonadal germ cell cancer (GGCC) is increased in selective subgroups, amongst others, defined patients with disorders of sex development (DSD). The increased risk is due to the presence of part of the Y chromosome, i.e., GonadoBlastoma on Y chromosome GBY region, as well as anatomical localization and degree of testicularization and maturation of the gonad. The latter specifically relates to the germ cells present being at risk when blocked in an embryonic stage of development. GGCC originates from either germ cell neoplasia in situ (testicular environment) or gonadoblastoma (ovarian-like environment). These precursors are characterized by presence of the markers OCT3/4 (POU5F1), SOX17, NANOG, as well as TSPY, and cKIT and its ligand KITLG. One of the aims is to stratify individuals with an increased risk based on other parameters than histological investigation of a gonadal biopsy. These might include evaluation of defined susceptibility alleles, as identified by Genome Wide Association Studies, and detailed evaluation of the molecular mechanism underlying the DSD in the individual patient, combined with DNA, mRNA, and microRNA profiling of liquid biopsies. This review will discuss the current opportunities as well as limitations of available knowledge in the context of predicting the risk of GGCC in individual patients.

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Germ cell tumors: Insights from the Drosophila ovary and the mouse testis

Cited by 16 publications

References 136 publications

The H3K9 methyltransferase SETDB1 maintains female identity in Drosophila germ cells

The H3K9 methyltransferase SETDB1 maintains female identity in Drosophila germ cells

CENP-C regulates centromere assembly, asymmetry and epigenetic age in Drosophila germline stem cells

Predicting Gonadal Germ Cell Cancer in People with Disorders of Sex Development; Insights from Developmental Biology

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