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Article ; Online: FGF-independent MEK1/2 signalling in the developing foetal testis is essential for male germline differentiation in mice

Rheannon O. Blücher / Rachel S. Lim / Ellen G. Jarred / Matthew E. Ritchie / Patrick S. Western

BMC Biology, Vol 21, Iss 1, Pp 1-

2023 Volume 22

Abstract: Abstract Background Disrupted germline differentiation or compromised testis development can lead to subfertility or infertility and are strongly associated with testis cancer in humans. In mice, SRY and SOX9 induce expression of Fgf9, which promotes ... ...

Abstract	Abstract Background Disrupted germline differentiation or compromised testis development can lead to subfertility or infertility and are strongly associated with testis cancer in humans. In mice, SRY and SOX9 induce expression of Fgf9, which promotes Sertoli cell differentiation and testis development. FGF9 is also thought to promote male germline differentiation but the mechanism is unknown. FGFs typically signal through mitogen-activated protein kinases (MAPKs) to phosphorylate ERK1/2 (pERK1/2). We explored whether FGF9 regulates male germline development through MAPK by inhibiting either FGF or MEK1/2 signalling in the foetal testis immediately after gonadal sex determination and testis cord formation, but prior to male germline commitment. Results pERK1/2 was detected in Sertoli cells and inhibition of MEK1/2 reduced Sertoli cell proliferation and organisation and resulted in some germ cells localised outside of the testis cords. While pERK1/2 was not detected in germ cells, inhibition of MEK1/2 after somatic sex determination profoundly disrupted germ cell mitotic arrest, dysregulated a broad range of male germline development genes and prevented the upregulation of key male germline markers, DPPA4 and DNMT3L. In contrast, while FGF inhibition reduced Sertoli cell proliferation, expression of male germline markers was unaffected and germ cells entered mitotic arrest normally. While male germline differentiation was not disrupted by FGF inhibition, a range of stem cell and cancer-associated genes were commonly altered after 24 h of FGF or MEK1/2 inhibition, including genes involved in the maintenance of germline stem cells, Nodal signalling, proliferation, and germline cancer. Conclusions Together, these data demonstrate a novel role for MEK1/2 signalling during testis development that is essential for male germline differentiation, but indicate a more limited role for FGF signalling. Our data indicate that additional ligands are likely to act through MEK1/2 to promote male germline differentiation and ...
Keywords	Germline development ; MEK1/2 ; FGF9 ; Testis ; Foetal gonad ; Sex differentiation ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Pharmacological inhibition of EZH2 disrupts the female germline epigenome

Lexie Prokopuk / Kirsten Hogg / Patrick S. Western

Clinical Epigenetics, Vol 10, Iss 1, Pp 1-

2018 Volume 12

Abstract: Abstract Background Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that ... ...

Abstract	Abstract Background Recently discovered drugs that target epigenetic modifying complexes are providing new treatment options for a range of cancers that affect patients of reproductive age. Although these drugs provide new therapies, it is likely that they will also affect epigenetic programming in sperm and oocytes. A promising target is Enhancer of Zeste 2 (EZH2), which establishes the essential epigenetic modification, H3K27me3, during development. Results In this study, we demonstrate that inhibition of EZH1/2 with the clinically relevant drug, tazemetostat, severely depletes H3K27me3 in growing oocytes of adult female mice. Moreover, EZH2 inhibition depleted H3K27me3 in primary oocytes and in fetal oocytes undergoing epigenetic reprogramming. Surprisingly, once depleted, H3K27me3 failed to recover in growing oocytes or in fetal oocytes. Conclusion Together, these data demonstrate that drugs targeting EZH2 significantly affect the germline epigenome and, based on genetic models with oocyte-specific loss of EZH2 function, are likely to affect outcomes in offspring.
Keywords	Germline ; Oocyte ; Pharmacology ; Epigenetic ; PRC2 ; H3K27me3 ; Medicine ; R ; Genetics ; QH426-470
Language	English
Publishing date	2018-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Out of sight, out of mind? Germ cells and the potential impacts of epigenomic drugs [version 1; referees

Ellen G. Jarred / Heidi Bildsoe / Patrick S. Western

F1000Research, Vol

3 approved]

2018 Volume 7

Abstract: Epigenetic modifications, including DNA methylation and histone modifications, determine the way DNA is packaged within the nucleus and regulate cell-specific gene expression. The heritability of these modifications provides a memory of cell identity and ...

Abstract	Epigenetic modifications, including DNA methylation and histone modifications, determine the way DNA is packaged within the nucleus and regulate cell-specific gene expression. The heritability of these modifications provides a memory of cell identity and function. Common dysregulation of epigenetic modifications in cancer has driven substantial interest in the development of epigenetic modifying drugs. Although these drugs have the potential to be highly beneficial for patients, they act systemically and may have “off-target” effects in other cells such as the patients’ sperm or eggs. This review discusses the potential for epigenomic drugs to impact on the germline epigenome and subsequent offspring and aims to foster further examination into the possible effects of these drugs on gametes. Ultimately, the information gained by further research may improve the clinical guidelines for the use of such drugs in patients of reproductive age.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Reduced PRC2 function alters male germline epigenetic programming and paternal inheritance

Jessica M. Stringer / Samuel C. Forster / Zhipeng Qu / Lexie Prokopuk / Moira K. O’Bryan / David K. Gardner / Stefan J. White / David Adelson / Patrick S. Western

BMC Biology, Vol 16, Iss 1, Pp 1-

2018 Volume 20

Abstract: Abstract Background Defining the mechanisms that establish and regulate the transmission of epigenetic information from parent to offspring is critical for understanding disease heredity. Currently, the molecular pathways that regulate epigenetic ... ...

Abstract	Abstract Background Defining the mechanisms that establish and regulate the transmission of epigenetic information from parent to offspring is critical for understanding disease heredity. Currently, the molecular pathways that regulate epigenetic information in the germline and its transmission to offspring are poorly understood. Results Here we provide evidence that Polycomb Repressive Complex 2 (PRC2) regulates paternal inheritance. Reduced PRC2 function in mice resulted in male sub-fertility and altered epigenetic and transcriptional control of retrotransposed elements in foetal male germ cells. Males with reduced PRC2 function produced offspring that over-expressed retrotransposed pseudogenes and had altered preimplantation embryo cleavage rates and cell cycle control. Conclusion This study reveals a novel role for the histone-modifying complex, PRC2, in paternal intergenerational transmission of epigenetic effects on offspring, with important implications for understanding disease inheritance.
Keywords	Germline ; Epigenetic reprogramming ; PRC2 ; H3K27me3 ; Paternal inheritance ; Fertility ; Biology (General) ; QH301-705.5
Subject code	590
Language	English
Publishing date	2018-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Esrp1 is a marker of mouse fetal germ cells and differentially expressed during spermatogenesis.

Shaghayegh Saeidi / Farnaz Shapouri / Robb U de Iongh / Franca Casagranda / Jessie M Sutherland / Patrick S Western / Eileen A McLaughlin / Mary Familari / Gary R Hime

PLoS ONE, Vol 13, Iss 1, p e

2018 Volume 0190925

Abstract: ESRP1 regulates alternative splicing, producing multiple transcripts from its target genes in epithelial tissues. It is upregulated during mesenchymal to epithelial transition associated with reprogramming of fibroblasts to iPS cells and has been linked ... ...

Abstract	ESRP1 regulates alternative splicing, producing multiple transcripts from its target genes in epithelial tissues. It is upregulated during mesenchymal to epithelial transition associated with reprogramming of fibroblasts to iPS cells and has been linked to pluripotency. Mouse fetal germ cells are the founders of the adult gonadal lineages and we found that Esrp1 mRNA was expressed in both male and female germ cells but not in gonadal somatic cells at various stages of gonadal development (E12.5-E15.5). In the postnatal testis, Esrp1 mRNA was highly expressed in isolated cell preparations enriched for spermatogonia but expressed at lower levels in those enriched for pachytene spermatocytes and round spermatids. Co-labelling experiments with PLZF and c-KIT showed that ESRP1 was localized to nuclei of both Type A and B spermatogonia in a speckled pattern, but was not detected in SOX9+ somatic Sertoli cells. No co-localization with the nuclear speckle marker, SC35, which has been associated with post-transcriptional splicing, was observed, suggesting that ESRP1 may be associated with co-transcriptional splicing or have other functions. RNA interference mediated knockdown of Esrp1 expression in the seminoma-derived Tcam-2 cell line demonstrated that ESRP1 regulates alternative splicing of mRNAs in a non-epithelial cell germ cell tumour cell line.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2018-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Loss of maternal EED results in postnatal overgrowth

Lexie Prokopuk / Jessica M. Stringer / Craig R. White / Rolf H. A. M. Vossen / Stefan J. White / Ana S. A. Cohen / William T. Gibson / Patrick S. Western

Clinical Epigenetics, Vol 10, Iss 1, Pp 1-

2018 Volume 14

Abstract: Abstract Background Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the ... ...

Abstract	Abstract Background Investigating how epigenetic information is transmitted through the mammalian germline is the key to understanding how this information impacts on health and disease susceptibility in offspring. EED is essential for regulating the repressive histone modification, histone 3 lysine 27 tri-methylation (H3K27me3) at many developmental genes. Results In this study, we used oocyte-specific Zp3-Cre recombinase (Zp3Cre) to delete Eed specifically in mouse growing oocytes, permitting the study of EED function in oocytes and the impact of depleting EED in oocytes on outcomes in offspring. As EED deletion occurred only in growing oocytes and females were mated to normal wild type males, this model allowed the study of oocyte programming without confounding factors such as altered in utero environment. Loss of EED from growing oocytes resulted in a significant overgrowth phenotype that persisted into adult life. Significantly, this involved increased adiposity (total fat) and bone mineral density in offspring. Similar overgrowth occurs in humans with Cohen-Gibson (OMIM 617561) and Weaver (OMIM 277590) syndromes, that result from de novo germline mutations in EED or its co-factor EZH2, respectively. Consistent with a role for EZH2 in human oocytes, we demonstrate that de novo germline mutations in EZH2 occurred in the maternal germline in some cases of Weaver syndrome. However, deletion of Ezh2 in mouse oocytes resulted in a distinct phenotype compared to that resulting from oocyte-specific deletion of Eed. Conclusions This study provides novel evidence that altering EED-dependent oocyte programming leads to compromised offspring growth and development in the next generation.
Keywords	Epigenetic inheritance ; Germ ; Oocyte ; Polycomb ; Histone ; Weaver ; Medicine ; R ; Genetics ; QH426-470
Language	English
Publishing date	2018-07-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: WNT/Î²-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary

Gustin, Sonja E / Kirsten Hogg / Jessica M. Stringer / Raphael H. Rastetter / Emanuele Pelosi / Denise C. Miles / Andrew H. Sinclair / Dagmar Wilhelm / Patrick S. Western

Developmental biology. 2016 Apr. 15, v. 412

2016

Abstract: Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct ... ...

Abstract	Sexual development is initiated through differentiation of testicular Sertoli cells or ovarian granulosa cells. Although these supporting cells are considered to develop from common bipotential precursors, recent evidence suggests that distinct supporting cell populations are present in the ovary, with one providing granulosa cells of the medullary follicles and the other providing granulosa cells of the cortical follicles, the latter of which support lifelong fertility. Here, we demonstrate that XX fetal gonads contain GATA4 expressing supporting cells that either enter mitotic arrest, or remain proliferative. Blocking WNT signalling reduces XX supporting cell proliferation, while stabilising Î²-catenin signalling promotes proliferation, indicating that the renewal of pre-granulosa cells is dependent on WNT/Î²-catenin signalling in the proliferative supporting cell population. In contrast, XX supporting cells express p27 and FOXL2 and are maintained in mitotic arrest. Although FOXL2 is required for maintaining high levels of p27 expression, it is dispensable for entry and maintenance of mitotic arrest in XX supporting cells. Combined our data suggest that both medullary and cortical precursors arise from a common GATA4 expressing cell type. In addition, this work indicates that a balance between supporting cell self-renewal and differentiation is maintained in the developing ovary by relative WNT/Î²-catenin and p27/FOXL2 activities. This study provides significant new insights into the origin and formation of ovarian follicles and evidence supporting a common fetal origin of medullary and cortical granulosa cells.
Keywords	GATA transcription factors ; Sertoli cells ; cell proliferation ; granulosa cells ; mitosis ; sexual development
Language	English
Dates of publication	2016-0415
Size	p. 250-260.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2016.02.024
Database	NAL-Catalogue (AGRICOLA)

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Article: Marker genes identify three somatic cell types in the fetal mouse ovary

Rastetter, Raphael H / Anne-Amandine Chassot / Dagmar Wilhelm / Huijun Chen / James S. Palmer / Marie-Christine Chaboissier / Pascal Bernard / Patrick S. Western / Robert G. Ramsay

Developmental biology. 2014 Oct. 15, v. 394, no. 2

2014

Abstract: The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries ... ...

Abstract	The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries during embryogenesis is critical for their function and the health of the individual in later life. Although the adult ovary has been investigated in great detail, we are only starting to understand the cellular and molecular biology of early ovarian development. Here we show that the adult stem cell marker Lgr5 is expressed in the cortical region of the fetal ovary and this expression is mutually exclusive to FOXL2. Strikingly, a third somatic cell population can be identified, marked by the expression of NR2F2, which is expressed in LGR5- and FOXL2 double-negative ovarian somatic cells. Together, these three marker genes label distinct ovarian somatic cell types. Using lineage tracing in mice, we show that Lgr5-positive cells give rise to adult cortical granulosa cells, which form the follicles of the definitive reserve. Moreover, LGR5 is required for correct timing of germ cell differentiation as evidenced by a delay of entry into meiosis in Lgr5 loss-of-function mutants, demonstrating a key role for LGR5 in the differentiation of pre-granulosa cells, which ensure the differentiation of oogonia, the formation of the definitive follicle reserve, and long-term female fertility.
Keywords	adult stem cells ; adults ; cell differentiation ; embryogenesis ; female fertility ; females ; genetic markers ; granulosa cells ; loss-of-function mutation ; meiosis ; mice ; molecular biology ; mutants ; oocytes ; oogonia ; ovarian development ; secretion ; sex hormones ; somatic cells
Language	English
Dates of publication	2014-1015
Size	p. 242-252.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1114-9
ISSN	1095-564X ; 0012-1606
ISSN (online)	1095-564X
ISSN	0012-1606
DOI	10.1016/j.ydbio.2014.08.013
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development.

Denise C Miles / Stephanie I Wakeling / Jessica M Stringer / Jocelyn A van den Bergen / Dagmar Wilhelm / Andrew H Sinclair / Patrick S Western

PLoS ONE, Vol 8, Iss 1, p e

2013 Volume 54606

Abstract: The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour ... ...

Abstract	The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgfβ family members has indicated that Tgfβ's are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin's, TGFβ's, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGFβ signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGFβ receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFβ and Activin signaling during testis formation and male germ cell development.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mitotic arrest in teratoma susceptible fetal male germ cells.

Patrick S Western / Rachael A Ralli / Stephanie I Wakeling / Camden Lo / Jocelyn A van den Bergen / Denise C Miles / Andrew H Sinclair

PLoS ONE, Vol 6, Iss 6, p e

2011 Volume 20736

Abstract: Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma ... ...

Abstract	Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma susceptible and non-susceptible mouse strains. This study examines the entry of fetal germ cells into the male pathway and mitotic arrest in 129T2/SvJ mice. We find that although the entry of fetal germ cells into mitotic arrest is similar between 129T2/SvJ, C57Bl/6 and CD1 mice, there were significant differences in the size and germ cell content of the testis cords in these strains. In 129T2/SvJ mice germ cell mitotic arrest involves upregulation of p27(KIP1), p15(INK4B), activation of RB, the expression of male germ cell differentiation markers NANOS2, DNMT3L and MILI and repression of the pluripotency network. The germ-line markers DPPA2 and DPPA4 show reciprocal repression and upregulation, respectively, while FGFR3 is substantially enriched in the nucleus of differentiating male germ cells. Further understanding of fetal male germ cell differentiation promises to provide insight into disorders of the testis and germ cell lineage, such as testis tumour formation and infertility.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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