PAX2+ Mesenchymal Origin of Gonadal Supporting Cells Is Conserved in Birds

During embryonic gonadal development, the supporting cell lineage is the first cell type to differentiate, giving rise to Sertoli cells in the testis and pre-granulosa cells in the ovary. These cells are thought to direct other gonadal cell lineages down the testis or ovarian pathways, including the germline. Recent research has shown that, in contrast to mouse, chicken gonadal supporting cells derive from a PAX2/OSR1/DMRT1/WNT4 positive mesenchymal cell population. These cells colonize the undifferentiated genital ridge during early gonadogenesis, around the time that germ cells migrate into the gonad. During the process of somatic gonadal sex differentiation, PAX2 expression is down-regulated in embryonic chicken gonads just prior to up-regulation of testis- and ovary-specific markers and prior to germ cell differentiation. Most research on avian gonadal development has focused on the chicken model, and related species from the Galloanserae clade. There is a lack of knowledge on gonadal sex differentiation in other avian lineages. Comparative analysis in birds is required to fully understand the mechanisms of avian sex determination and gonadal differentiation. Here we report the first comparative molecular characterization of gonadal supporting cell differentiation in birds from each of the three main clades, Galloanserae (chicken and quail), Neoaves (zebra finch) and Palaeognathe (emu). Our analysis reveals conservation of PAX2+ expression and a mesenchymal origin of supporting cells in each clade. Moreover, down-regulation of PAX2 expression precisely defines the onset of gonadal sex differentiation in each species. Altogether, these results indicate that gonadal morphogenesis is conserved among the major bird clades.

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YAP creates epiblast responsiveness to inductive signals for germ cell fate

Development ◽

10.1242/dev.199732 ◽

2021 ◽

Author(s):

Saya Kagiwada ◽

Shinya Aramaki ◽

Guangming Wu ◽

Borami Shin ◽

Eva Kutejova ◽

...

Keyword(s):

Cell Differentiation ◽

Germ Cell ◽

Signaling Pathway ◽

Cell Fate ◽

Cell Lineage ◽

Signaling Molecules ◽

Hippo Signaling ◽

Epiblast Stem Cells ◽

Germ Cell Differentiation ◽

Cell Induction

The germ cell lineage in mammals is induced by the stimulation of pluripotent epiblast cells with signaling molecules. Previous studies have suggested that the germ cell differentiation competence or responsiveness of epiblast cells to signaling molecules is established and maintained in epiblast cells of a specific differentiation state. However, the molecular mechanism underlying this process has not been well defined. Here, using the differentiation model of epiblast stem cells (EpiSCs), we have shown that two defined EpiSC lines have robust germ cell differentiation competence. However, another defined EpiSC line has no competence. By evaluating the molecular basis of EpiSCs with distinct germ cell differentiation competence, we identified YAP/YAP1/YAP65, an intracellular mediator of the Hippo signaling pathway, as a critical mediator for establishing germ cell induction. Strikingly, deletion of YAP severely affected responsiveness to inductive stimuli, leading to a defect in WNT target activation and germ cell differentiation. In conclusion, we propose that the Hippo/YAP signaling pathway creates a potential for germ cell fate induction via mesodermal WNT signaling in pluripotent epiblast cells.

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RUNX1 maintains the identity of the fetal ovary through an interplay with FOXL2

Nature Communications ◽

10.1038/s41467-019-13060-1 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Barbara Nicol ◽

Sara A. Grimm ◽

Frédéric Chalmel ◽

Estelle Lecluze ◽

Maëlle Pannetier ◽

...

Keyword(s):

Transcription Factor ◽

Granulosa Cell ◽

Sertoli Cells ◽

Transcriptional Control ◽

Cell Lineage ◽

Supporting Cell ◽

Supporting Cells ◽

Fate Specification ◽

Fetal Ovary

Abstract Sex determination of the gonads begins with fate specification of gonadal supporting cells into either ovarian pre-granulosa cells or testicular Sertoli cells. This fate specification hinges on a balance of transcriptional control. Here we report that expression of the transcription factor RUNX1 is enriched in the fetal ovary in rainbow trout, turtle, mouse, goat, and human. In the mouse, RUNX1 marks the supporting cell lineage and becomes pre-granulosa cell-specific as the gonads differentiate. RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity and combined loss of RUNX1 and FOXL2 results in masculinization of fetal ovaries. At the chromatin level, RUNX1 occupancy overlaps partially with FOXL2 occupancy in the fetal ovary, suggesting that RUNX1 and FOXL2 target common sets of genes. These findings identify RUNX1, with an ovary-biased expression pattern conserved across species, as a regulator in securing the identity of ovarian-supporting cells and the ovary.

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In vitro germ cell differentiation during sex differentiation in a teleost fish

The International Journal of Developmental Biology ◽

10.1387/ijdb.082836tk ◽

2010 ◽

Vol 54 (1) ◽

pp. 105-111 ◽

Cited By ~ 12

Author(s):

Tohru Kobayashi

Keyword(s):

Cell Differentiation ◽

Germ Cell ◽

Teleost Fish ◽

Sex Differentiation ◽

Germ Cell Differentiation

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Single-cell roadmap of human gonadal development

10.21203/rs.3.rs-496470/v1 ◽

2021 ◽

Author(s):

Roser Vento-Tormo ◽

Luz Garcia-Alonso ◽

Valentina Lorenzi ◽

Cecilia Mazzeo ◽

Carmen Sancho-Serra ◽

...

Keyword(s):

Single Cell ◽

Granulosa Cells ◽

Mammalian Species ◽

Supporting Cell ◽

Gonadal Development ◽

Chromatin Accessibility ◽

In Vitro Models ◽

Second Trimester ◽

Germ Cell Differentiation

Abstract Gonadal development is a complex process that involves sex determination followed by divergent maturation into ovaries or testes. Historically, limited tissue accessibility and lack of reliable in vitro models have impeded our understanding of human gonadogenesis, despite its importance in gonadal pathologies and infertility. Here, we generated a comprehensive map of first- and second-trimester gonadal development using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and imaging. Using this approach, we identified novel transcription factors and cell states in human germ and supporting cell lineages. We compared them with other mammalian species and found primate-specific regulatory programmes. Our data identified cell context–specific interactions shaping sex specification and development of human germ cells. We defined a novel bipotent progenitor cell (LGR5+, TSPAN8+) in late embryos that can differentiate into early Sertoli in males or pre-granulosa cells in females. In fetal ovaries, we defined two subsets of pre-granulosa cells supporting germ-cell differentiation and distributed across the cortico-medullary axis. We also found a subset of developing granulosa cells appearing during the second trimester of pregnancy that is involved in follicular assembly. In fetal testes, we defined a novel supporting population (sPAX8 cells) located at the poles of the developing testis cords. We also found two tissue-resident myeloid populations that we named microglia-like and SIGLEC15+ fetal testicular macrophages. This study provides an unprecedented spatiotemporal map of human gonadal differentiation that can be utilised as a blueprint for in vitro gametogenesis.

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Crosstalk Between Retinoic Acid and Sex-Related Genes Controls Germ Cell Fate and Gametogenesis in Medaka

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.613497 ◽

2021 ◽

Vol 8 ◽

Author(s):

Mateus C. Adolfi ◽

Amaury Herpin ◽

Anabel Martinez-Bengochea ◽

Susanne Kneitz ◽

Martina Regensburger ◽

...

Keyword(s):

Retinoic Acid ◽

Cell Differentiation ◽

Sex Determination ◽

Germ Cell ◽

Cell Fate ◽

Germ Cells ◽

Sex Differentiation ◽

Model Species ◽

Fish Model ◽

Germ Cell Differentiation

Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of Stra8. In this study, we used a fish model species for sex determination and lacking the stra8 gene, the Japanese medaka (Oryzias latipes), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of dmrt1a and amh. Disruption of the RA degrading enzyme gene cyp26a1 induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of cyp26a1–/–adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a stra8 independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes.

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RUNX1 safeguards the identity of the fetal ovary through an interplay with FOXL2

10.1101/598607 ◽

2019 ◽

Author(s):

Barbara Nicol ◽

Sara A. Grimm ◽

Frederic Chalmel ◽

Estelle Lecluze ◽

Maëlle Pannetier ◽

...

Keyword(s):

Granulosa Cell ◽

Sertoli Cells ◽

Transcriptional Control ◽

Cell Lineage ◽

Supporting Cell ◽

Supporting Cells ◽

Fate Specification ◽

Ovarian Granulosa Cells ◽

Fetal Ovary

AbstractSex determination of the gonads begins with fate specification of gonadal supporting cells into either ovarian granulosa cells or testicular Sertoli cells. This process of fate specification hinges on a balance of transcriptional control. We discovered that expression of the transcription factor RUNX1 is enriched in the fetal ovary in rainbow trout, turtle, mouse, goat and human. In the mouse, RUNX1 marks the supporting cell lineage and becomes granulosa cell-specific as the gonads differentiate. RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity, and combined loss of RUNX1 and FOXL2 results in masculinization of the fetal ovaries. At the chromatin level, RUNX1 occupancy overlaps partially with FOXL2 occupancy in the fetal ovary, suggesting that RUNX1 and FOXL2 target a common set of genes. These findings identify RUNX1, with an ovary-biased pattern conserved across species, as a novel regulator in securing the identity of ovarian supporting cells and the ovary.

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The molecular genetics of Sry and its role in mammalian sex determination

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.1995.0153 ◽

1995 ◽

Vol 350 (1333) ◽

pp. 205-214 ◽

Cited By ~ 32

Keyword(s):

Sex Determination ◽

Target Genes ◽

Gene Action ◽

Human Gene ◽

Cell Lineage ◽

Supporting Cell ◽

Gonadal Development ◽

Genital Ridge ◽

Testis Differentiation ◽

Testicular Differentiation

The process of sex determination, by which is meant the decision as to whether an embryo develops as a male or a female, is considered as a paradigm of how gene action can influence developmental fate. In mammals the decision is dependent on the action of the testis determining gene present on the Y chromosome, now known to be the gene Sry . Sry is expressed for only a brief period in the mouse embryo and must act to initiate rather than maintain the pathway of gene activity required for testis differentiation. It probably acts within cells of the supporting cell lineage to direct their differentiation into Sertoli cells, rather than the granulosa cells characteristic of the ovary. Other lineages in the gonad then follow the male pathway. The nature of the Sry transcript in the genital ridge of mice has been determined and compared with that from the human gene which is dramatically different. The expression of Sry has been carefully examined during the critical stages of genital ridge development and compared to the expression of a number of other genes involved in gonadal development and male development such as that for anti-Mullerian hormone. This has defined the period in which Sry must act to between 11 and 11.5 days post coitum . The expression of Sry has also been examined in cases of sex reversal in the mouse. There is a dependence on level of expression and extent of testicular differentiation that suggests thresholds for both the amount of SRY per cell and the number of cells expressing the gene. The SRY protein interacts with DNA through an HMG box type of DNA binding domain, however at present no definite target genes have been found. Progress on strategies to find such genes is discussed.

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Natural selection at the cellular level: insights from male germ cell differentiation

Cell Death and Differentiation ◽

10.1038/s41418-021-00812-0 ◽

2021 ◽

Author(s):

Daniel H. Nguyen ◽

Diana J. Laird

Keyword(s):

Natural Selection ◽

Cell Differentiation ◽

Germ Cell ◽

Cellular Level ◽

Male Germ Cell ◽

Germ Cell Differentiation

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RIP140 Represses Intestinal Paneth Cell Differentiation and Interplays with SOX9 Signaling in Colorectal Cancer

Cancers ◽

10.3390/cancers13133192 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3192

Author(s):

Antoine Gleizes ◽

Mouna Triki ◽

Sandrine Bonnet ◽

Naomi Baccari ◽

Gabriel Jimenez-Dominguez ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Differentiation ◽

Paneth Cell ◽

Wnt Signaling Pathway ◽

Cell Lineage ◽

Human Colon ◽

Luciferase Reporter ◽

Loss Of Function ◽

Sox9 Expression ◽

Human Colon Cancer

RIP140 is a major transcriptional coregulator of gut homeostasis and tumorigenesis through the regulation of Wnt/APC signaling. Here, we investigated the effect of RIP140 on Paneth cell differentiation and its interplay with the transcription factor SOX9. Using loss of function mouse models, human colon cancer cells, and tumor microarray data sets we evaluated the role of RIP140 in SOX9 expression and activity using RT-qPCR, immunohistochemistry, luciferase reporter assays, and GST-pull down. We first evidence that RIP140 strongly represses the Paneth cell lineage in the intestinal epithelium cells by inhibiting Sox9 expression. We then demonstrate that RIP140 interacts with SOX9 and inhibits its transcriptional activity. Our results reveal that the Wnt signaling pathway exerts an opposite regulation on SOX9 and RIP140. Finally, the levels of expression of RIP140 and SOX9 exhibit a reverse response and prognosis value in human colorectal cancer biopsies. This work highlights an intimate transcriptional cross-talk between RIP140 and SOX9 in intestinal physiopathology.

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