ORCID Profile
0000-0003-2867-7438
Current Organisation
Universidad de Santiago de Chile Facultad de Química y Biología
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Developmental Genetics (incl. Sex Determination) | Gene Expression (incl. Microarray and other genome-wide approaches) | Genetics | Animal Developmental and Reproductive Biology | Other Biological Sciences | Environmental Management | Cell Development, Proliferation and Death | Climate Change Processes | Global Change Biology
ANZSRC Socio-Economic Objective (SEO)
Reproductive System and Disorders | Expanding Knowledge in the Biological Sciences | Animal Production and Animal Primary Products not elsewhere classified | Effects of Climate Change and Variability on Antarctic and Sub-Antarctic Environments (excl. Social Impacts) | Ecosystem Assessment and Management of Antarctic and Sub-Antarctic Environments | Environmental Policy, Legislation and Standards not elsewhere classified |
Related Links
Publications
Endogenous Nodal signaling regulates germ cell potency during mammalian testis development
Publisher: The Company of Biologists
Date: 15-11-2012
DOI: 10.1242/DEV.083006
Abstract: Germ cells, the embryonic precursors of sperm or oocytes, respond to molecular cues that regulate their sex-specific development in the fetal gonads. In males in particular, the balance between continued proliferation and cell fate commitment is crucial: defects in proliferation result in insufficient spermatogonial stem cells for fertility, but escape from commitment and prolonged pluripotency can cause testicular germ cell tumors. However, the factors that regulate this balance remain unidentified. Here, we show that signaling by the TGFβ morphogen Nodal and its co-receptor Cripto is active during a crucial window of male germ cell development. The Nodal pathway is triggered when somatic signals, including FGF9, induce testicular germ cells to upregulate Cripto. Germ cells of mutant mice with compromised Nodal signaling showed premature differentiation, reduced pluripotency marker expression and a reduced ability to form embryonic germ (EG) cell colonies in vitro. Conversely, human testicular tumors showed upregulation of NODAL and CRIPTO that was proportional to invasiveness and to the number of malignant cells. Thus, Nodal signaling provides a molecular control mechanism that regulates male germ cell potency in normal development and testicular cancer.
Antagonistic regulation ofCyp26b1by transcription factors SOX9/SF1 and FOXL2 during gonadal development in mice
Publisher: Wiley
Date: 14-07-2011
DOI: 10.1096/FJ.11-184333
Gonads–Müllerian Ducts
Publisher: Elsevier
Date: 2004
Searching for missing pieces of the sex-determination puzzle
Publisher: Wiley
Date: 2001
DOI: 10.1002/JEZ.1095
Abstract: Little is known of the mechanisms whereby the mammalian indifferent gonad develops into a testis or ovary. In XY in iduals, Sry, the mammalian testis-determining gene, is expressed in the pre-Sertoli cells, which then differentiate into Sertoli cells. Other cell types, which include the germ cells, the steroidogenic cells and the connective tissue cells, must then be instructed to develop in a male-specific manner. Although some genes involved in sex-determination and differentiation processes have been identified, we know little of how they interact and cooperate to orchestrate the development of a testis or ovary. We have initiated an expression-screening program designed to identify additional genes, known or novel, which play a role in these processes. This approach is based on our belief that many of the genes we seek will be expressed in a sex-specific manner during the period of sex-determination and differentiation. Most of the genes identified previously are transcription factors and so we aim, in particular, to find genes involved in cell-to-cell communication, signal transduction, and transcriptional regulation, downstream of the differentiation of Sertoli cells. We have used a suppression subtractive-hybridization method to generate male- and female-enriched probes and libraries. Clones are validated as being sex-specific in their expression patterns by array screening and in situ hybridization. Here we report on our progress to date and the general applicability of the approach for studies in other systems. J. Exp. Zool. 290:517-522, 2001.
Expression and Functional Analysis of Dkk1 during Early Gonadal Development
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000327709
Abstract: WNT signalling plays a central role in mammalian sex determination by promoting ovarian development and repressing aspects of testis development in the early gonad. Dickkopf homolog 1 (DKK1) is a WNT signalling antagonist that plays critical roles in multiple developmental systems by modulating WNT activity. Here, we examined the role of DKK1 in mouse sex determination and early gonadal development. i Dkk1 /i mRNA was upregulated sex-specifically during testis differentiation, suggesting that DKK1 could repress WNT signalling in the developing testis. However, we observed overtly normal testis development in i Dkk1 /i -null XY gonads, and found no significant upregulation of i Axin2 /i or i Sp5 /i that would indicate increased canonical WNT signalling. Nor did we find significant differences in expression of key markers of testis and ovarian development. We propose that DKK1 may play a protective role that is not unmasked by loss-of-function in the absence of other stressors.
Prolonged prenatal hypoxia selectively disrupts collecting duct patterning and postnatal function in male mouse offspring
Publisher: Wiley
Date: 05-07-2018
DOI: 10.1113/JP275918
Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility
Publisher: Oxford University Press (OUP)
Date: 05-01-2016
Abstract: Studies report that fetal exposure to paracetamol/acetaminophen by maternal consumption can interfere with male reproductive development. Moreover, recent biomonitoring data report widespread presence of paracetamol in German and Danish populations, suggesting exposure via secondary (nonpharmaceutical) sources, such as metabolic conversion from the ubiquitous industrial compound aniline. In this study, we investigated the extent to which paracetamol and aniline can interfere with female reproductive development. Intrauterine exposure to paracetamol by gavage of pregnant dams resulted in shortening of the anogenital distance in adult offspring, suggesting that fetal hormone signaling had been disturbed. Female offspring of paracetamol-exposed mothers had ovaries with diminished follicle reserve and reduced fertility. Fetal gonads of exposed animals had also reduced gonocyte numbers, suggesting that the reduced follicle count in adults could be due to early disruption of germ cell development. However, ex vivo cultures of ovaries from 12.5 days post coitum fetuses showed no decrease in proliferation or expression following exposure to paracetamol. This suggests that the effect of paracetamol occurs prior to this developmental stage. Accordingly, using embryonic stem cells as a proxy for primordial germ cells we show that paracetamol is an inhibitor of cellular proliferation, but without cytotoxic effects. Collectively, our data show that intrauterine exposure to paracetamol at levels commonly observed in pregnant women, as well as its precursor aniline, may block primordial germ cell proliferation, ultimately leading to reduced follicle reserves and compromised reproductive capacity later in life.
Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9
Publisher: Springer Science and Business Media LLC
Date: 14-12-2018
DOI: 10.1038/S41467-018-07784-9
Abstract: Disorders of sex development (DSDs) are conditions affecting development of the gonads or genitalia. Variants in two key genes, SRY and its target SOX9 , are an established cause of 46,XY DSD, but the genetic basis of many DSDs remains unknown. SRY-mediated SOX9 upregulation in the early gonad is crucial for testis development, yet the regulatory elements underlying this have not been identified in humans. Here, we identified four DSD patients with overlapping duplications or deletions upstream of SOX9 . Bioinformatic analysis identified three putative enhancers for SOX9 that responded to different combinations of testis-specific regulators. All three enhancers showed synergistic activity and together drive SOX9 in the testis. This is the first study to identify SOX9 enhancers that, when duplicated or deleted, result in 46,XX or 46,XY sex reversal, respectively. These enhancers provide a hitherto missing link by which SRY activates SOX9 in humans, and establish SOX9 enhancer mutations as a significant cause of DSD.
Male sex determination: insights into molecular mechanisms
Publisher: Medknow
Date: 19-12-2011
DOI: 10.1038/AJA.2011.169
Structure–function analysis of mouse Sry reveals dual essential roles of the C-terminal polyglutamine tract in sex determination
Publisher: Proceedings of the National Academy of Sciences
Date: 29-07-2014
Abstract: The sex-determining factor SRY is thought to function by up-regulating expression of its key target gene SRY-box 9 ( SOX9 ) in pre-Sertoli cells of the developing gonads, but evidence for a transactivation domain is lacking for human SRY and is limited to in vitro evidence for mouse Sry. The latter is unusual in possessing a polyglutamine tract at its C terminus. We demonstrate, using a combination of biochemical, cell-based, and transgenic mouse assays, that this domain plays essential roles in both protein stabilization and transactivation of Sox9 , and is required for male sex determination in mice. Our data indicate that mouse Sry has evolved a novel bifunctional module, revealing an unexpected level of plasticity of sex-determining mechanisms even among mammals.
It Is Hot in the Sun: Antarctic Mosses Have High Temperature Optima for Photosynthesis Despite Cold Climate
Publisher: Frontiers Media SA
Date: 07-08-2020
The PCNA-associated factor KIAA0101/p15 binds the potential tumor suppressor product p33ING1b
Publisher: Elsevier BV
Date: 2006
DOI: 10.1016/J.YEXCR.2005.09.020
Abstract: The KIAA0101 15(PAF)/OEATC-1 protein was initially isolated in a yeast two-hybrid screen for proliferating cell nuclear antigen (PCNA) binding partners, and was shown to bind PCNA competitively with the cell cycle regulator p21(WAF). PCNA is involved in DNA replication and damage repair. Using polyclonal antisera raised against a p15(PAF) fusion protein, we have shown that in a range of mammalian tumor and non-tumor cell lines the endogenous p15(PAF) protein localises to the nucleus and the mitochondria. Under normal conditions no co-localisation with PCNA could be detected, however following exposure to UV it was possible to co-immunoprecipitate p15(PAF) and PCNA from a number of cell lines, suggesting a UV-enhanced association of the two proteins. Overexpression of p15(PAF) in mammalian cells was also found to protect cells from UV-induced cell death. Based on similarities between the behaviour of p15(PAF) and the potential tumor suppressor product p33ING1b, we have further shown that these two proteins interact in the same complex in cell cultures. This suggests that p15(PAF) forms part of a larger protein complex potentially involved in the regulation of DNA repair, apoptosis and cell cycle progression.
SOX30 is required for male fertility in mice
Publisher: Springer Science and Business Media LLC
Date: 15-12-2017
DOI: 10.1038/S41598-017-17854-5
Abstract: Male infertility is a major and growing problem and, in most cases, the specific root cause is unknown. Here we show that the transcription factor SOX30 plays a critical role in mouse spermatogenesis. Sox30 -null mice are healthy and females are fertile, but males are sterile. In the absence of Sox30 meiosis initiates normally in both sexes but, in males, germ cell development arrests during the post-meiotic round spermatid period. In the mutant testis, acrosome and axoneme development are aberrant, multinucleated germ cells (symplasts) form and round spermatids unable to process beyond step 3 of spermiogenesis. No elongated spermatids nor spermatozoa are produced. Thus, Sox30 represents a rare ex le of a gene for which loss of function results in a complete arrest of spermatogenesis at the onset of spermiogenesis. Our results suggest that SOX30 mutations may underlie some instances of unexplained non-obstructive azoospermia in humans.
Retinoic acid, meiosis and germ cell fate in mammals
Publisher: The Company of Biologists
Date: 10-2007
DOI: 10.1242/DEV.001107
Abstract: Although mammalian sex is determined genetically, the sex-specific development of germ cells as sperm or oocytes is initiated by cues provided by the gonadal environment. During embryogenesis, germ cells in an ovary enter meiosis, thereby committing to oogenesis. By contrast, germ cells in a testicular environment do not enter meiosis until puberty. Recent findings indicate that the key to this sex-specific timing of meiosis entry is the presence or absence of the signaling molecule retinoic acid. Although this knowledge clarifies a long-standing mystery in reproductive biology, it also poses many new questions, which we discuss in this review.
Onset of meiosis in the chicken embryo; evidence of a role for retinoic acid
Publisher: Springer Science and Business Media LLC
Date: 17-09-2008
Abstract: Meiosis in higher vertebrates shows a dramatic sexual dimorphism: germ cells enter meiosis and arrest at prophase I during embryogenesis in females, whereas in males they enter mitotic arrest during embryogenesis and enter meiosis only after birth. Here we report the molecular analysis of meiosis onset in the chicken model and provide evidence for conserved regulation by retinoic acid. Meiosis in the chicken embryo is initiated late in embryogenesis (day 15.5), relative to gonadal sex differentiation (from day 6). Meiotic germ cells are first detectable only in female gonads from day 15.5, correlating with the expression of the meiosis marker, SCP3. Gonads isolated from day 10.5 female embryos and grown in serum-free medium could still initiate meiosis at day 16.5, suggesting that this process is controlled by an endogenous clock in the germ cells themselves, and/or that germ cells are already committed to meiosis at the time of explantation. Early commitment is supported by the analysis of chicken STRA8 , a pre-meiotic marker shown to be essential for meiosis in mouse. Chicken STRA8 is expressed female-specifically from embryonic day 12.5, preceding morphological evidence of meiosis at day 15.5. Previous studies have shown that, in the mouse embryo, female-specific induction of STRA8 and meiosis are triggered by retinoic acid. A comprehensive analysis of genes regulating retinoic acid metabolism in chicken embryos reveals dynamic expression in the gonads. In particular, the retinoic acid-synthesising enzyme, RALDH2 , is expressed in the left ovarian cortex at the time of STRA8 up-regulation, prior to meiosis. This study presents the first molecular analysis of meiosis onset in an avian embryo. Although aspects of avian meiosis differ from that of mammals, a role for retinoic acid may be conserved.
Expression of the tudor-related gene Tdrd5 during development of the male germline in mice
Publisher: Elsevier BV
Date: 10-2004
DOI: 10.1016/J.MODGEP.2004.04.002
Abstract: Homologues of Drosophila germ cell determinant genes such as vasa, nanos and tudor have recently been implicated in development of the male germline in mice. In the present study, the mouse gene encoding Tudor domain containing protein 5 (TDRD5) was isolated from a 12.5-13.5 days post coitum (dpc) male-enriched subtracted cDNA library. Whole-mount in situ hybridization analysis of Tdrd5 expression in the mouse embryonic gonad indicated that this gene is upregulated in the developing testis from 12.5 dpc, with expression levels remaining higher in testis than ovary throughout embryogenesis. Expression of Tdrd5 was absent in testes isolated from We/We embryos, which lack germ cells. In situ hybridization (ISH) on cryosectioned 13.5 dpc testes suggests that expression of Tdrd5, like that of Oct4, is restricted to germ cells. Northern hybridization analysis of expression in adult tissues indicated that Tdrd5 is expressed in the testis only, implying that expression of this gene is restricted to the male germline throughout development to adulthood.
A Site-Specific, Single-Copy Transgenesis Strategy to Identify 5′ Regulatory Sequences of the Mouse Testis-Determining Gene Sry
Publisher: Public Library of Science (PLoS)
Date: 17-04-2014
Genetic variants within the genus Echinococcus identified by mitochondrial DNA sequencing
Publisher: Elsevier BV
Date: 09-1992
DOI: 10.1016/0166-6851(92)90109-W
Abstract: The pattern of species and strain variation within the genus Echinococcus is complex and controversial. In an attempt to characterise objectively the various species and strains, the sequence of a region of the mitochondrial cytochrome c oxidase subunit I (CO1) gene was determined for 56 Echinococcus isolates. Eleven different genotypes were detected, including 7 within Echinococcus granulosus, and these were used to categorise the isolates. The 4 generally accepted Echinococcus species were clearly distinguishable using this approach. In addition, the consensus view of the strain pattern within E. granulosus, based on a variety of criteria of differentiation, was broadly upheld. Very little variation was detected within Echinococcus multilocularis. Remarkable intra-strain homogeneity was found at the DNA sequence level. This region of the rapidly evolving mitochondrial genome is useful as a marker of species and strain identity and as a preliminary indication of evolutionary ergence within the genus Echinococcus.
Mice null for Sox18 are viable and display a mild coat defect
Publisher: Informa UK Limited
Date: 12-2000
Purification and Transcriptomic Analysis of Mouse Fetal Leydig Cells Reveals Candidate Genes for Specification of Gonadal Steroidogenic Cells1
Publisher: Oxford University Press (OUP)
Date: 06-2015
DOI: 10.1095/BIOLREPROD.115.128918
Abstract: Male sex determination hinges on the development of testes in the embryo, beginning with the differentiation of Sertoli cells under the influence of the Y-linked gene SRY. Sertoli cells then orchestrate fetal testis formation including the specification of fetal Leydig cells (FLCs) that produce steroid hormones to direct virilization of the XY embryo. As the majority of XY disorders of sex development (DSDs) remain unexplained at the molecular genetic level, we reasoned that genes involved in FLC development might represent an unappreciated source of candidate XY DSD genes. To identify these genes, and to gain a more detailed understanding of the regulatory networks underpinning the specification and differentiation of the FLC population, we developed methods for isolating fetal Sertoli, Leydig, and interstitial cell-enriched subpopulations using an Sf1-eGFP transgenic mouse line. RNA sequencing followed by rigorous bioinformatic filtering identified 84 genes upregulated in FLCs, 704 genes upregulated in nonsteroidogenic interstitial cells, and 1217 genes upregulated in the Sertoli cells at 12.5 days postcoitum. The analysis revealed a trend for expression of components of neuroactive ligand interactions in FLCs and Sertoli cells and identified factors potentially involved in signaling between the Sertoli cells, FLCs, and interstitial cells. We identified 61 genes that were not known previously to be involved in specification or differentiation of FLCs. This dataset provides a platform for exploring the biology of FLCs and understanding the role of these cells in testicular development. In addition, it provides a basis for targeted studies designed to identify causes of idiopathic XY DSD.
Author Correction: Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects (Nature Communications, (2023), 14, 1, (3403), 10.1038/s41467-023-39040-0)
Publisher: Springer Science and Business Media LLC
Date: 15-06-2023
Sex determination in mammalian germ cells: extrinsic versus intrinsic factors
Publisher: Bioscientifica
Date: 06-2010
DOI: 10.1530/REP-10-0075
Abstract: Mammalian germ cells do not determine their sexual fate based on their XX or XY chromosomal constitution. Instead, sexual fate is dependent on the gonadal environment in which they develop. In a fetal testis, germ cells commit to the spermatogenic programme of development during fetal life, although they do not enter meiosis until puberty. In a fetal ovary, germ cells commit to oogenesis by entering prophase of meiosis I. Although it was believed previously that germ cells are pre-programmed to enter meiosis unless they are actively prevented from doing so, recent results indicate that meiosis is triggered by a signaling molecule, retinoic acid (RA). Meiosis is avoided in the fetal testis because a male-specifically expressed enzyme actively degrades RA during the critical time period. Additional extrinsic factors are likely to influence sexual fate of the germ cells, and in particular, we postulate that an additional male-specific fate-determining factor or factors is involved. The full complement of intrinsic factors that underlie the competence of gonadal germ cells to respond to RA and other extrinsic factors is yet to be defined.
Regulation of male sexual development bySry andSox9
Publisher: Wiley
Date: 2001
DOI: 10.1002/JEZ.1089
Abstract: Sry, a gene from the Y chromosome, is known to initiate testis formation and subsequent male differentiation in mammals. A related gene, Sox9, also plays a critical role in testis determination, possibly in all vertebrates. A number of models have been presented regarding the molecular modes of action of these two genes. However, details regarding their regulation, regulatory target genes, and interacting protein factors and co-factors have not been established with any certainty. In this review, we examine new evidence and re-examine existing evidence bearing on these issues, in an effort to build up an integrative model of the network of gene activity centred around Sry and Sox9. J. Exp. Zool. 290:463-474, 2001.
Expression of a linear Sry transcript in the mouse genital ridge
Publisher: Springer Science and Business Media LLC
Date: 08-1995
DOI: 10.1038/NG0895-480
Abstract: Sry is the Y-chromosomal gene that is pivotal in the determination of sex in mammals, however the structure of the Sry transcript produced in the embryo has not been determined. We show here that the transcript expressed in the developing mouse gonad at the sex determining stage of development is linear, polyadenylated and encoded by a single exon, in contrast to the circular, apparently untranslated transcript produced in adult testes. The linear transcript was not detected in any other fetal tissue nor in any adult tissue tested, and was expressed only in the genital ridge portion of the urogenital ridge. The spatial and temporal profile of Sry expression suggests that its role in the mouse fetus is limited to initiating Sertoli cell development during testis determination.
Extensive vascularization of developing mouse ovaries revealed by caveolin-1 expression
Publisher: Wiley
Date: 27-08-2002
DOI: 10.1002/DVDY.10128
Abstract: Expression screening for genes preferentially expressed in mouse fetal ovaries relative to testes identified Cav-1 as a candidate female-specific gene. Cav-1 encodes caveolin-1, a component of the cell membrane invaginations known as caveolae, which are involved in lipid regulation and signal transduction. In situ hybridization revealed high levels of Cav-1 mRNA in developing ovaries, compared with moderate or low levels in testes. Analysis of caveolin-1 protein distribution by immunofluorescence showed this difference to be due to the development of a dense and complex vascular network in the developing ovary. These observations point to a higher degree of differentiation and organization of the early stage mammalian ovary than previously suspected.
Retinoid Signaling Determines Germ Cell Fate in Mice
Publisher: American Association for the Advancement of Science (AAAS)
Date: 28-04-2006
Abstract: Germ cells in the mouse embryo can develop as oocytes or spermatogonia, depending on molecular cues that have not been identified. We found that retinoic acid, produced by mesonephroi of both sexes, causes germ cells in the ovary to enter meiosis and inititate oogenesis. Meiosis is retarded in the fetal testis by the action of the retinoid-degrading enzyme CYP26B1, ultimately leading to spermatogenesis. In testes of Cyp26b1 -knockout mouse embryos, germ cells enter meiosis precociously, as if in a normal ovary. Thus, precise regulation of retinoid levels during fetal gonad development provides the molecular control mechanism that specifies germ cell fate.
ALDH1A1 provides a source of meiosis-inducing retinoic acid in mouse fetal ovaries
Publisher: Springer Science and Business Media LLC
Date: 19-02-2016
DOI: 10.1038/NCOMMS10845
Abstract: Substantial evidence exists that during fetal ovarian development in mammals, retinoic acid (RA) induces germ cells to express the pre-meiotic marker Stra8 and enter meiosis, and that these effects are prevented in the fetal testis by the RA-degrading P450 enzyme CYP26B1. Nonetheless, the role of RA has been disputed principally because germ cells in embryos lacking two major RA-synthesizing enzymes, ALDH1A2 and ALDH1A3, remain able to enter meiosis. Here we show that a third RA-synthesizing enzyme, ALDH1A1, is expressed in fetal ovaries, providing a likely source of RA in the absence of ALDH1A2 and ALDH1A3. In ovaries lacking ALDH1A1, the onset of germ cell meiosis is delayed. Our data resolve the conundrum posed by conflicting published data sets and reconfirm the model that meiosis is triggered by endogenous RA in the developing ovary.
New insights into SRY regulation through identification of 5' conserved sequences
Publisher: Springer Science and Business Media LLC
Date: 14-10-2008
Abstract: SRY is the pivotal gene initiating male sex determination in most mammals, but how its expression is regulated is still not understood. In this study we derived novel SRY 5' flanking genomic sequence data from bovine and caprine genomic BAC clones. We identified four intervals of high homology upstream of SRY by comparison of human, bovine, pig, goat and mouse genomic sequences. These conserved regions contain putative binding sites for a large number of known transcription factor families, including several that have been implicated previously in sex determination and early gonadal development. Our results reveal potentially important SRY regulatory elements, mutations in which might underlie cases of idiopathic human XY sex reversal.
Initiating Meiosis: The Case for Retinoic Acid1
Publisher: Oxford University Press (OUP)
Date: 02-2012
On the role of germ cells in mammalian gonad development: quiet passengers or back-seat drivers?
Publisher: Bioscientifica
Date: 04-2015
DOI: 10.1530/REP-14-0663
Abstract: In addition to their role as endocrine organs, the gonads nurture and protect germ cells, and regulate the formation of gametes competent to convey the genome to the following generation. After sex determination, gonadal somatic cells use several known signalling pathways to direct germ cell development. However, the extent to which germ cells communicate back to the soma, the molecular signals they use to do so and the significance of any such signalling remain as open questions. Herein, we review findings arising from the study of gonadal development and function in the absence of germ cells in a range of organisms. Most published studies support the view that germ cells are unimportant for foetal gonadal development in mammals, but later become critical for stabilisation of gonadal function and somatic cell phenotype. However, the lack of consistency in the data, and clear differences between mammals and other vertebrates and invertebrates, suggests that the story may not be so simple and would benefit from more careful analysis using contemporary molecular, cell biology and imaging tools.
Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
Publisher: Springer Science and Business Media LLC
Date: 09-06-2023
DOI: 10.1038/S41467-023-39040-0
Abstract: Squamous cell carcinoma antigen recognized by T cells 3 ( SART3 ) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine in iduals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY in iduals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome ( I ntellectual disability, N eurodevelopmental defects and D evelopmental delay with 46,X Y GON adal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for in iduals born with this condition.
Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse
Publisher: The Company of Biologists
Date: 03-2021
DOI: 10.1242/DEV.194977
Abstract: In mice, the entry of germ cells into meiosis crucially depends on the expression of stimulated by retinoic acid gene 8 (Stra8). Stra8 is expressed specifically in pre-meiotic germ cells of females and males, at fetal and postnatal stages, respectively, but the mechanistic details of its spatiotemporal regulation are yet to be defined. In particular, there has been considerable debate regarding whether retinoic acid is required, in vivo, to initiate Stra8 expression in the mouse fetal ovary. We show that the distinctive anterior-to-posterior pattern of Stra8 initiation, characteristic of germ cells in the fetal ovary, is faithfully recapitulated when 2.9 kb of the Stra8 promoter is used to drive eGFP expression. Using in vitro transfection assays of cutdown and mutant constructs, we identified two functional retinoic acid responsive elements (RAREs) within this 2.9 kb regulatory element. We also show that the transcription factor DMRT1 enhances Stra8 expression, but only in the presence of RA and the most proximal RARE. Finally, we used CRISPR/Cas9-mediated targeted mutation studies to demonstrate that both RAREs are required for optimal Stra8 expression levels in vivo.
Generation and characterization of a Ddx4‐iCre transgenic line for deletion in the germline beginning at genital ridge colonization
Publisher: Wiley
Date: 24-01-2023
DOI: 10.1002/DVG.23511
Abstract: Germline‐specific Cre lines are useful for analyses of primordial germ cell, spermatogonial and oogonial development, but also for whole‐body deletions when transmitted through subsequent generations. Several germ cell specific Cre mouse strains exist, with various degrees of specificity, efficiency, and temporal activation. Here, we describe the CRISPR/Cas9 targeted insertion of an improved Cre ( iCre ) sequence in‐frame at the 3′ end of the Ddx4 locus to generate the Ddx4‐P2A‐iCre allele. Our functional assessment of this new allele, designated Ddx4 iCreJoBo , reveals that Cre activity begins in PGCs from at least E10.5, and that it achieves higher efficiency for early gonadal (E10.5–12.5) germline deletion when compared to the inducible Oct4 CreERT2 line. We found the Ddx4 iCreJoBo allele to be hypomorphic for Ddx4 expression and homozygous males, but not females, were infertile. Using two reporter lines ( R26R LacZ and R26R tdTomato ) and a floxed gene of interest ( Cripto flox ) we found ectopic activity in multiple organs global recombination (a common feature of germline Cre alleles) varies from 10 to 100%, depending on the particular floxed allele. There is a strong maternal effect, and therefore it is preferable for Ddx4 iCreJoBo to be inherited from the male parent if ubiquitous deletion is not desired. With these limitations considered, we describe the Ddx4 iCreJoBo line as useful for germline studies in which early gonadal deletion is required.
Characterisation of Crim1 expression in the developing mouse urogenital tract reveals a sexually dimorphic gonadal expression pattern
Publisher: Wiley
Date: 2000
DOI: 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1072>3.0.CO;2-I
Profiles of Gonadal Gene Expression in the Developing Bovine Embryo
Publisher: S. Karger AG
Date: 2009
DOI: 10.1159/000252791
Abstract: Our current understanding of the molecular basis of sex determination and gonadal development in humans is mostly an extrapolation of knowledge gained from studies in the mouse. However, the timing of gene expression in the mouse is unusual among mammals, and it is therefore important that data from other models are also available to help elucidate this pivotal process in human development. Here we describe the sequence of molecular and morphological events marking testis differentiation in bovine embryos. The genital ridges first appeared at CRL 12 (day 32). i SRY /i expression began at CRL 18 (day 37) and peaked at CRL 20 (day 39), leading to a cascade of regulatory, signaling, and steroidogenic gene expression at later stages, detected by quantitative real-time RT-PCR and immunohistochemistry. Testis cords were distinguishable at CRL 27 (day 42). We conclude that the timing of gene expression observed in developing human embryos is much more similar to bovine development than it is to the mouse. Therefore, i Bos taurus /i may represent a useful model in which to study gene expression during sex determination, relevant to human development.
FGF9 Suppresses Meiosis and Promotes Male Germ Cell Fate in Mice
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.DEVCEL.2010.08.010
Abstract: Sex determination of mammalian germ cells occurs during fetal development and depends on signals from gonadal somatic cells. Previous studies have established that retinoic acid (RA) triggers ovarian germ cells to enter meiosis and thereby commit to oogenesis, whereas in the developing testis, the enzyme CYP26B1 degrades RA and germ cells are not induced to enter meiosis. Using in vitro and in vivo models, we demonstrate that fibroblast growth factor 9 (FGF9) produced in the fetal testis acts directly on germ cells to inhibit meiosis in addition, FGF9 maintains expression of pluripotency-related genes and upregulates markers associated with male germ cell fate. We conclude that two independent and mutually antagonistic pathways involving RA and FGF9 act in concert to determine mammalian germ cell sexual fate commitment and support a model in which the mitosis/meiosis switch is robustly controlled by both positive and negative regulatory factors.
Culturing murine embryonic organs: Pros, cons, tips and tricks.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.DIFF.2016.01.008
Abstract: There are three established techniques described for ex vivo culture of the early embryonic organs: filter culture, agar block culture and hanging drop culture. Each of these protocols has advantages and disadvantages here we assess the merits of each approach. Agar block culture has a long history and has been well described. This method results in good embryonic organ morphology. Filter culture has been used to culture a number of different embryonic organs and there are a variety of filter choices available. The key disadvantage of agar-block and filter based culture is that the large amount of media required can make the approach expensive, especially if biologicals such as growth factors are necessary in addition, using these methods it can be difficult to track particular s les. Hanging drop culture is most commonly used to enable the aggregation of embryonic stem cells into embryoid bodies but it has also been employed for ex vivo organ culture. This method requires only 40μL of media per drop and isolates every organ to a trackable unit. We describe each of these methods and the use of different medias and provide the user with a matrix to help determine the optimal culture method for their needs. Glass-based culture methods required for live imaging are not discussed here.
Nodal/Cripto signaling in fetal male germ cell development: implications for testicular germ cell tumors
Publisher: UPV/EHU Press
Date: 2013
Abstract: Testicular cancer is the most frequent cancer in young men aged 15-40 years and accounts for 1% of all cancer diagnosed in males. Testicular germ cell tumors (TGCT) encompass a broad group of cancers, each displaying different levels of pluripotency and differentiation as well as malignancy potential. The TGCT cell of origin is thought to be a fetal germ cell that failed to correctly differentiate during development: this is known as the fetal origins hypothesis. This theory predicts that developmental pathways that control germ cell pluripotency or differentiation may be involved in the malignant transformation of these cells. Recently the Nodal/Cripto signaling pathway, known to control pluripotency and differentiation in embryonic stem (ES) cells, was implicated in regulating normal male fetal germ cell pluripotency. Although genes of this pathway are not normally expressed in germ cells during adult life, ectopic expression of this pathway was detected in several sub-groups of TGCTs. In this review, we consider the evidence for the fetal origins of TGCT and discuss the implications of Nodal/Cripto signaling in various aspects of germ cell development and cancer progression.
Characterisation of urogenital ridge gene expression in the human embryonal carcinoma cell line NT2/D1
Publisher: S. Karger AG
Date: 2007
DOI: 10.1159/000100033
Abstract: The study of the mammalian sex-determining pathway has been h ered by the lack of cell culture systems to investigate the underlying molecular relationships between sex-determining genes. Recent approaches using high-throughput genome-wide studies have revealed a number of sexually dimorphic genes expressed in the developing mouse gonad. Here, we investigated a human testicular cell line in terms of its expression of known sex-determining genes and newly identified candidates. The human embryonal carcinoma cell line NT2/D1 was screened for the expression of 46 genes with known or potential roles in the sex-determining and differentiation pathway. Forty genes tested were expressed in NT2/D1 cells including the testis-determining genes i SRY /i , i SOX9 /i , i SF-1 /i , i DHH /i and i FGF9 /i . Genes not expressed included i WT1 /i , i DAX1 /i and the ovary-specific genes i FOXL2 /i and i WNT4 /i . Cell-specific markers demonstrate that NT2/D1 cells reflect a number of cell types in the gonad including Sertoli, Leydig and germ cells. Our results suggest that male pathways initiated by SRY, SOX9 and SF-1 remain intact in these cells. Lack of expression of ovary-specific genes is consistent with a commitment of these cells to the male lineage. Manipulation of gene expression in this cell line could be an important new in vitro tool for the discovery of new human sex-determining genes.
Male-specific expression of Aldh1a1 in mouse and chicken fetal testes: Implications for retinoid balance in gonad development
Publisher: Wiley
Date: 17-07-2008
DOI: 10.1002/DVDY.22024
Abstract: Balanced production and degradation of retinoids is important in regulating development of several organ systems in the vertebrate embryo. Among these, it is known that retinoic acid (RA), and the retinoid-catabolyzing enzyme CYP26B1 together regulate the sex-specific behavior of germ cells in developing mouse gonads. We report here that the gene encoding a cytosolic class-1 aldehyde dehydrogenase, ALDH1A1, a weak catalyst of RA production, is strongly expressed in a male-specific manner in somatic cells of the developing mouse testis, beginning shortly after Sry expression is first detectable. This expression pattern is conserved in the developing male gonad of the chicken and is dependent on the testis-specific transcription factor SOX9. Our data suggest that low levels of RA may be required for early developmental events in the testis, or that Aldh1a1 expression in the fetus may prefigure a later requirement for ALDH1A1 in regulating spermatogenesis postnatally.
SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse
Publisher: Elsevier BV
Date: 03-1997
Author Correction: Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9 (Nature Communications, (2018), 9, 1, (5319), 10.1038/s41467-018-07784-9)
Publisher: Springer Science and Business Media LLC
Date: 23-07-2019
DOI: 10.1038/S41467-019-11310-W
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Control of retinoid levels by CYP26B1 is important for lymphatic vascular development in the mouse embryo
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.YDBIO.2013.12.008
Abstract: During embryogenesis, lymphatic endothelial progenitor cells first arise from a subset of blood vascular endothelial cells in the dorsolateral aspects of the cardinal veins. The molecular cues responsible for defining the regionalisation of such a discrete pool of progenitors remain uncharacterised. Here we identify a novel function for CYP26B1, an enzyme known to play a role in tissue morphogenesis by fine-tuning retinoic acid (RA) concentration, in regulating lymphangiogenesis. Cyp26b1-null mice, in which RA levels are elevated, exhibited an increased number of lymphatic endothelial progenitor cells in the cardinal veins, together with hyperplastic, blood filled lymph sacs and hyperplastic dermal lymphatic vessels. Conversely, mice over-expressing Cyp26b1 had hypoplastic lymph sacs and lymphatic vessels. Our data suggest that RA clearance by CYP26B1 in the vicinity of lymphatic endothelial progenitor cells is important for determining the position and size of the progenitor pool specified. Our studies identify a genetic pathway that underpins the architecture of the developing lymphatics and define CYP26B1 as a novel modulator of lymphatic vascular patterning.
Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2018
DOI: 10.1101/331090
Abstract: The nuclear receptor NR5A1 (also known as Ad4BP, or SF1) is essential for the initial steps of mammalian gonadal development. The Nr5a1 gene is equally expressed in XX and XY gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We recently reported a case of 46, XX disorder of sex development (DSD) in which ectopically expressed NR5A1 in XX gonads led to an ovo-testicular phenotype, suggesting that excess NR5A1 can direct the development of immature XX gonads towards testicular formation. However, a direct causal relationship has not been demonstrated in an animal model. Here, using a Wt1-BAC (bacterial artificial chromosome) transgene system, we generated two lines of mice overexpressing Nr5a1 in the fetal gonads at different levels. One of these lines (Tg-S), highly expressing Nr5a1, revealed that enforced Nr5a1 expression alone is insufficient to switch the fate of the 46,XX gonads toward testicular formation in mice. In the other line (Tg-A) expressing Nr5a1 at lower level, ovarian development was compromised, with multi-oocyte follicles, reduced number of matured follicles, and impaired expression of Wnt4, resulting in late onset infertility at 20 weeks after birth. The phenotype was similar to that of genetically modified mice with impaired Notch signaling. Indeed, the expression level of Notch2 and 3 was significantly reduced in Tg-A mice, and the ovarian phenotype in Tg-A mice was almost completely rescued by in utero treatment with a Notch2 agonist HMN2-29. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by fine tuning of Notch signaling levels. Sexual development is a process of differentiation from undifferentiated bipotential gonads, and insight into sexual differentiation will bring important new knowledge to our understanding of organogenesis. The nuclear receptor NR5A1 which is essential for mammalian gonadal development, is equally expressed in both gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We have recently demonstrated that this down-regulation is mediated by ovarian transcription factor, Forkhead box L2 (FOXL2). This finding raised two key questions, whether Nr5a1 can function as a male sex-determining factor, and whether the repression is essential for appropriate ovarian development. By generating two lines Tg mice in XX gonads with different enforced expression levels of Nr5a1, our present study revealed that alterations in Nr5a1 dosage, either reduced or excessive, result in pathological effects in ovarian development and female fertility, indicating that the precise control of Nr5a1 at the transcriptional level is essential for optimal ovarian development. We envisage that the improved understanding of how this pathway regulates ovarian development and female fertility would aid the development of artificial somatic ovarian cells, which in turn may provide a valuable treatment option in reproductive medicine. BAC bacterial artificial chromosome dpc days post coitum FOXL2 Forkhead box L2 HSD hydroxysteroid dehydrogenase IF Immunofluorescence MOFs multiple oocyte follicles PFA paraformaldehyde qRT-PCR Quantitative real-time PCR Rps29 Ribosomal protein S29 SRY sex-determining region Y
Agarose/gelatin immobilisation of tissues or embryo segments for orientated paraffin embedding and sectioning.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.DIFF.2015.12.001
Abstract: The technique described in this protocol allows the user to position small tissues in the optimal orientation for paraffin embedding and sectioning by first immobilising the tissue in an agarose/gelatin cube. This method is an adaptation of methods used for early embryos and can be used for any small tissues or embryo segments. Processing of larger tissue sections using molds to create agarose/gelatin blocks has been described previously this detailed protocol provides a method for dealing with much smaller tissues or embryos (≤5mm). The tissue is briefly fixed then an agarose/gelatin drop is created to surround the tissue. The tissue can be orientated as per the user's preference in the drop before it sets as is carved into a cube with a domed top. The cube is then dehydrated and goes through the embedding and sectioning process. The domed cube is easy to orientate when embedding the tissue in a wax block giving the user assured orientation of the small tissue for sectioning. Additionally, the agarose/gelatin cube is easy to see in the unmolded wax once embedded, making the region of interest easy to identify.
Transcription Factors ER71/ETV2 and SOX9 Participate in a Positive Feedback Loop in Fetal and Adult Mouse Testis
Publisher: Elsevier BV
Date: 07-2012
The matricellular protein SPARC is internalized in Sertoli, Leydig, and germ cells during testis differentiation
Publisher: Wiley
Date: 2006
DOI: 10.1002/MRD.20394
Abstract: The gene encoding the matricellular protein secreted protein, acidic and rich in cysteine (SPARC) was identified in a screen for genes expressed sex-specifically during mouse gonad development, as being strongly upregulated in the male gonad from very early in testis development. We present here a detailed analysis of SPARC gene and protein expression during testis development, from 11.5 to 15.5 days post coitum (dpc). Section in situ hybridization analysis revealed that SPARC mRNA is expressed by the Sertoli cells in the testis cords and the fetal Leydig cells, found within the interstitial space between the testis cords. Immunodetection with anti-SPARC antibody showed that the protein was located inside the testis cords, within the cytoplasm of Sertoli and germ cells. In the interstitium, SPARC was present intracellularly within the Leydig cells. The internalization of SPARC in Sertoli, Leydig, and germ cells suggests that it plays an intracellular regulatory role in these cell types during fetal testis development.
Pisrt1, a gene implicated in XX sex reversal, is expressed in gonads of both sexes during mouse development
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.YMGME.2005.06.013
Abstract: XX sex reversal syndromes not involving Sry provide an opportunity to identify and study genes important for sexual development. The polled intersex syndrome (PIS) in goats, which shares some features with blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) in humans, exemplifies such syndromes. BPES is caused by defects in the forkhead transcription factor gene FOXL2, while PIS is caused by a large deletion of goat chromosome 1q43 that affects transcription of the genes Pisrt1 and Foxl2. Pisrt1 is a non-translated gene that has a sexually dimorphic expression pattern in goats. Here, we describe the structure and expression of the mouse Pisrt1 locus, to investigate its likely role in ovarian development more broadly in mammals. This gene showed some sequence similarity, and was found in a similar genomic context, to its goat and human orthologues. Expression analyses indicated that Pisrt1 is transcribed, and its mRNA polyadenylated and exported to the cytoplasm, but no significant open reading frames were found in a 1.5kb mouse genomic region corresponding to goat Pisrt1. Pisrt1 transcripts were expressed very broadly among tissues of the developing mouse embryo, and at similar levels in male and female gonads at each stage examined, as determined by in situ hybridisation and RT-PCR. This profile of expression suggests that Pisrt1 is unlikely to contribute to sex-specific events during gonadal development in mice and that ergent pathways of ovarian development operate among different mammalian species.
<i>Dppa3</i> is a marker of pluripotency and has a human homologue that is expressed in germ cell tumours
Publisher: S. Karger AG
Date: 2003
DOI: 10.1159/000074346
Abstract: We identified a transcript named 11M2 on the basis of its strong male-specific expression pattern in the developing mouse gonad. 11M2 was found to be expressed by gonad primordial germ cells (PGCs) of both sexes and down-regulated in female PGCs as they enter prophase I of the first meiotic ision, similar to the expression of i Oct4 /i . Mouse EST analysis revealed expression only in early-stage embryos, embryonic stem cells and pre-meiotic germ cells. 11M2 corresponds to a recently reported gene variously known as PGC7, i stella /i or i Dppa3 /i . We have identified the human orthologue of i Dppa3 /i and find by human EST analysis that it is expressed in human testicular germ cell tumours but not in normal human somatic tissues. The expression patterns of mouse and human DPPA3, in undifferentiated embryonic cells, embryonic germ cells and adult germ cell tumours, together suggest a role for this gene in maintaining cell pluripotentiality.
Germ cells influence cord formation and Leydig cell gene expression during mouse testis development.
Publisher: Wiley
Date: 08-01-2016
DOI: 10.1002/DVDY.24371
Abstract: It is widely accepted that, during the development of testes in the mammalian embryo, male germ cells are influenced by signals from the surrounding somatic cells, but not vice versa, so that germ cells are dispensable for the formation of testes. We now demonstrate that development of the mouse fetal testis is compromised in the absence of germ cells. Using two- and three-dimensional imaging techniques, we reveal that W(e)/W(e) mutant testes devoid of germ cells have misshapen and poorly organized cords. We also found that mutant gonads have fewer Sertoli cells than normal and that the Leydig cells express key markers at higher than normal levels. These observations point to the existence of germ cell-derived signals that directly or indirectly affect the Sertoli and Leydig cell populations, and provide a new paradigm for the organogenesis of the mammalian testes.
Sry requires a CAG repeat domain for male sex determination in Mus musculus
Publisher: Springer Science and Business Media LLC
Date: 08-1999
DOI: 10.1038/11981
Abstract: SRY, the mammalian Y-chromosomal sex-determining gene, encodes a protein characterized by a DNA-binding and -bending domain referred to as the HMG box. Despite the pivotal role of this gene, only the HMG box region has been conserved through evolution, suggesting that SRY function depends solely on the HMG box and therefore acts as an architectural transcription factor. In mice (genus Mus) Sry also includes a large CAG trinucleotide repeat region encoding a carboxy-terminal glutamine-rich domain that acts as a transcriptional trans-activator in vitro. The absence of this or any other potential trans-activating domain in other mammals, however, has raised doubts as to its biological relevance. To test directly whether the glutamine-rich region is required for Sry function in vivo, we created truncation mutations of the Mus musculus musculus Sry gene and tested their ability to induce testis formation in XX embryos using a transgenic mouse assay. Sry constructs that encode proteins lacking the glutamine-rich region were unable to effect male sex determination, in contrast to their wild-type counterparts. We conclude that the glutamine-rich repeat domain of the mouse Sry protein has an essential role in sex determination in vivo, and that Sry may act via a fundamentally different biochemical mechanism in mice compared with other mammals.
HMG box transcription factor gene Hbp1 is expressed in germ cells of the developing mouse testis
Publisher: Wiley
Date: 22-04-2004
DOI: 10.1002/DVDY.20053
Abstract: HMG box containing protein 1 (HBP1) is a high mobility group domain transcriptional repressor that regulates proliferation in differentiated tissues. We have found mouse Hbp1 to be expressed strongly in the embryonic mouse testis from approximately 12.5 days post coitum, compared with low levels of expression in the embryonic ovary. Expression of Hbp1 is maintained in the developing testis beyond the onset of spermatogenesis after birth. Whole-mount in situ hybridisation analysis showed that expression of Hbp1 in the XY gonad is localized within the developing testis cords, the precursors of the seminiferous tubules. Expression of Hbp1 is not apparent in testis cords of gonads from homozygous W(e) mutant embryos, which lack germ cells. In situ hybridisation analysis on cryosectioned embryonic testis indicated that Hbp1 expression resembles that of the germ cell marker Oct4. We conclude that Hbp1 is up-regulated specifically in germ cells of the developing XY gonad. The expression of Hbp1 in XY germ cells appears to correlate with the onset of mitotic arrest in these cells.
Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signaling during mammalian sex determination
Publisher: Elsevier BV
Date: 11-2005
DOI: 10.1016/J.YDBIO.2005.08.039
Abstract: We have raised an antibody specifically recognizing endogenous mouse SRY protein and used it to investigate the molecular and cellular mode of action of SRY in testis determination. We find that expression of SRY protein closely mirrors the expression of Sry mRNA in mouse genital ridges and is detectable for 6 to 8 h after the mRNA ceases to be detectable. The subset of somatic cells that expresses SRY begins to express SOX9 almost immediately. Since these SOX9-positive cells go on to develop as Sertoli cells, it appears that SRY expression marks the pre-Sertoli cell lineage and leads to up-regulation of Sox9 expression cell-autonomously. However, a small proportion of SOX9-positive cells did not appear to express SRY, possibly reflecting the additional involvement of paracrine signaling in activating Sox9 transcription in these cells. We confirmed by ex vivo cell mixing experiments that SRY is able to engage receptor-mediated signaling to up-regulate Sox9 expression. Finally, we showed by employing specific inhibitors that the causative signaling molecule is prostaglandin D2 (PGD2) and that PGD2 can induce Sox9 transcription in cultured XX gonads. Our data indicate a mechanism whereby Sry uses both a cell-autonomous mechanism and a PGD2-mediated signaling mechanism to stimulate expression of Sox9 and induce the differentiation of Sertoli cells in vivo.
Bayesian methods for comparing species physiological and ecological response curves
Publisher: Elsevier BV
Date: 07-2016
Sex determination in mammalian germ cells
Publisher: Medknow
Date: 2015
Regulation of germ cell meiosis in the fetal ovary
Publisher: UPV/EHU Press
Date: 2012
Abstract: Fertility depends on correct regulation of meiosis, the special form of cell ision that gives rise to haploid gametes. In female mammals, germ cells enter meiosis during fetal ovarian development, while germ cells in males avoid entering meiosis until puberty. Decades of research have shown that meiotic entry, and germ cell sex determination, are not initiated intrinsically within the germ cells. Instead, meiosis is induced by signals produced by the surrounding somatic cells. More recently, retinoic acid (RA), the active derivative of vitamin A, has been implicated in meiotic induction during fetal XX and postnatal XY germ cell development. Evidence for an intricate system of RA synthesis and degradation in the fetal ovary and testis has emerged, explaining past observations of infertility in vitamin A-deficient rodents. Here we review how meiosis is triggered in fetal ovarian germ cells, paying special attention to the role of RA in this process.
Evaluation of candidate markers for the peritubular myoid cell lineage in the developing mouse testis
Publisher: Bioscientifica
Date: 10-2005
DOI: 10.1530/REP.1.00718
Abstract: Despite the importance of peritubular myoid (PM) cells in the histogenesis of the fetal testis, understanding the origin and function of these cells has been h ered by the lack of suitable markers. The current study was aimed at identifying molecular markers for PM cells during the early stages of testis development in the mouse embryo. Expression of candidate marker genes was tested by section in situ hybridisation, in some instances followed by immunofluorescent detection of protein products. Collagen type-I , inhibin β A , caldesmon 1 and tropomyosin 1 were found to be expressed by early-stage PM cells. These markers were also expressed in subsets of interstitial cells, most likely reflecting their common embryological provenance from migrating mesonephric cells. Although not strictly specific for PM cells, these markers are likely to be useful in studying the biology of early PM cells in the fetal testis.
Control of mammalian germ cell entry into meiosis
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.MCE.2013.09.026
Abstract: Germ cells are unique in undergoing meiosis to generate oocytes and sperm. In mammals, meiosis onset is before birth in females, or at puberty in males, and recent studies have uncovered several regulatory steps involved in initiating meiosis in each sex. Evidence suggests that retinoic acid (RA) induces expression of the critical pre-meiosis gene Stra8 in germ cells of the fetal ovary, pubertal testis and adult testis. In the fetal testis, CYP26B1 degrades RA, while FGF9 further antagonises RA signalling to suppress meiosis. Failsafe mechanisms involving Nanos2 may further suppress meiosis in the fetal testis. Here, we draw together the growing knowledge relating to these meiotic control mechanisms, and present evidence that they are co-ordinately regulated and that additional factors remain to be identified. Understanding this regulatory network will illuminate not only how the foundations of mammalian reproduction are laid, but also how mis-regulation of these steps can result in infertility or germline tumours.
Precious Cargo: Regulation of Sex-Specific Germ Cell Development in Mice
Publisher: S. Karger AG
Date: 31-08-2012
DOI: 10.1159/000342072
Abstract: Although mammalian sex determination is normally specified genetically by an XX or XY chromosome complement, germ cells develop as sperm or oocytes in response to molecular cues provided by the gonadal somatic cells. In an ovary, germ cells enter meiosis during fetal life, thereby committing to oogenesis. In a testis, germ cells do not enter meiosis until after birth, at puberty. Recent findings indicate that, in mice, the sex-specific timing of entry into meiosis is governed by the balance between 2 secreted signalling molecules, retinoic acid (RA), which promotes entry into meiosis, and fibroblast growth factor 9 (FGF9), which counteracts RA. The combined action of these 2 molecular regulators provides a safety mechanism to guard against germ cell dysregulation that can lead to infertility or germ cell cancers.
Retinoic Acid Antagonizes Testis Development in Mice.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.CELREP.2018.06.111
Abstract: Mammalian sex determination depends on a complex interplay of signals that promote the bipotential fetal gonad to develop as either a testis or an ovary, but the details are incompletely understood. Here, we investigated whether removal of the signaling molecule retinoic acid (RA) by the degradative enzyme CYP26B1 is necessary for proper development of somatic cells of the testes. Gonadal organ culture experiments suggested that RA promotes expression of some ovarian markers and suppresses expression of some testicular markers, acting downstream of Sox9. XY Cyp26b1-null embryos, in which endogenous RA is not degraded, develop mild ovotestes, but more important, steroidogenesis is impaired and the reproductive tract feminized. Experiments involving purified gonadal cells showed that these effects are independent of germ cells and suggest the direct involvement of the orphan nuclear receptor DAX1. Our results reveal that active removal of endogenous RA is required for normal testis development in the mouse.
Phylogeny of the SOX Family of Developmental Transcription Factors Based on Sequence and Structural Indicators
Publisher: Elsevier BV
Date: 11-2000
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Universidad De Santiago De Chile Facultad De Química Y Biología
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