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Search Results: 1 - 10 of 165847 matches for " Andrew H. Sinclair "
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Eleven years of sexual discovery
Andrew Sinclair
Genome Biology , 2001, DOI: 10.1186/gb-2001-2-7-reports4017
Abstract: Eleven years after the discovery of the Y-linked testis-determining gene, SRY, 'sex workers' gathered at the Novartis Foundation in London to discuss the state of the field. Novartis Foundation Symposia differ from many other types of meeting in being closed, small (only 15 speakers and 15 observers), with extensive discussion, and focusing primarily on gaps in our knowledge - which in this case were many.The key step in mammalian sex determination is the development of the undifferentiated embryonic gonads into either testes or ovaries. We have known since 1990 that the SRY gene is the critical switch leading to testis development. SRY encodes a member of the SOX family of transcription factors and its name denotes 'sex-determining region of the Y chromosome'. Mutations in SRY result in XY individuals developing as females, and transgenic XX mice ectopically expressing Sry develop into sex-reversed males. This means that among all the Y-chromosome-derived sequences, SRY is the only one that is both required and sufficient to initiate male sex determination.As SRY is clearly critical in this process, much discussion revolved around its possible function. Robin Lovell-Badge (National Institute for Medical Research, London, UK) took us through the key experiments in mice that defined the function of SRY and pointed out the many structural and regulatory differences between Sry in mouse and SRY in humans. Vince Harley (Prince Henry's Institute, Melbourne, Australia) reviewed mutation and gel-shift (protein-DNA interaction) data confirming the critical role of one portion of SRY, namely the HMG box motif. The HMG box is essential for SRY to bind and bend DNA as well as for transporting the protein into the nucleus. Among mammals, SRY is poorly conserved outside the HMG box. Jenny Graves (Australian National University, Canberra, Australia) confirmed the long-held suspicion that SRY is not present in the monotremes (egg-laying mammals: platypus and echidna). This means t
Onset of meiosis in the chicken embryo; evidence of a role for retinoic acid
Craig A Smith, Kelly N Roeszler, Josephine Bowles, Peter Koopman, Andrew H Sinclair
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-85
Abstract: 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.One of the most fundamental developmental events in vertebrate embryos is the sexually dimorphic regulation of germ cell fate. In male mammals, the germ cells become incorporated into developing seminiferous cords of the testis during embryogenesis, where they enter mitotic arrest as prospermatogonia [1]. This quiescent state is thought to be induced by a signal from the adjacent Sertoli cells of the testis cords [2]. In contrast, germ cells in the female gonad enter the early stages of meiosis during embryonic life, arresting at prophase I as oocytes. Earl
Cloning and expression of R-Spondin1 in different vertebrates suggests a conserved role in ovarian development
Craig A Smith, Christina M Shoemaker, Kelly N Roeszler, Joanna Queen, David Crews, Andrew H Sinclair
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-72
Abstract: Gonadal RSPO1 gene expression is female up-regulated in the embryonic gonads in each species at the onset of sexual differentiation. In the mouse gonad, Rspo1 mRNA is expressed in the somatic cell lineage at the time of ovarian differentiation (E12.5–E15.5), with little expression in germ cells. However, the protein is localised in the cytoplasm and at the cell surface of both somatic (pre-follicular) and germ cells. In the chicken embryo, RSPO1 expression becomes elevated in females at the time of ovarian differentiation, coinciding with female-specific activation of the FOXL2 gene and estrogen synthesis. RSPO1 protein in chicken is localised in the outer cortical zone of the developing ovary, the site of primordial follicle formation and germ cell differentiation. Inhibition of estrogen synthesis with a specific aromatase inhibitor results in a decline in chicken RSPO1 expression, indicating that RSPO1 is influenced by estrogen. In the red-eared slider turtle, which exhibits temperature-dependent sex determination, up-regulation of RSPO1 occurs during the temperature-sensitive period, when gonadal development is responsive to temperature. Accordingly, RSPO1 expression is temperature-responsive, and is down-regulated in embryos shifted from female- to male-producing incubation temperatures.These results indicate that RSPO1 is up-regulated in the embryonic gonads of female vertebrates with different sex-determining mechanisms. In all instances, RSPO1 is expressed in the incipient ovary. These findings suggest that R-SPONDIN1 is an ancient, conserved part of the vertebrate ovary-determining pathway.Sex determination in vertebrate embryos results in either testis or ovary development. In most mammals, the Y-linked SRY gene initiates testicular development by directing Sertoli cell differentiation and the organization of seminiferous cords [1-5]. Leydig and other cell types then differentiate around the cords, testosterone is released and male development is elaborated
Rapid high-throughput analysis of DNaseI hypersensitive sites using a modified Multiplex Ligation-dependent Probe Amplification approach
Thomas Ohnesorg, Stefanie Eggers, Wouter N Leonhard, Andrew H Sinclair, Stefan J White
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-412
Abstract: We have developed a modified Multiplex Ligation-dependent Probe Amplification (MLPA) approach for the identification and analysis of genomic regulatory regions. The utility of this approach was demonstrated by simultaneously analysing 20 loci from the ENCODE project for DNaseI hypersensitivity in a range of different cell lines. We were able to obtain reproducible results with as little as 5 × 104 cells per DNaseI treatment. Our results broadly matched those previously reported by the ENCODE project, and both technical and biological replicates showed high correlations, indicating the sensitivity and reproducibility of this method.This new method will considerably facilitate the identification and analysis of DNaseI hypersensitive sites. Due to the multiplexing potential of MLPA (up to 50 loci can be examined) it is possible to analyse dozens of DNaseI hypersensitive sites in a single reaction. Furthermore, the high sensitivity of MLPA means that fewer than 105 cells per DNaseI treatment can be used, allowing the discovery and analysis of tissue specific regulatory regions without the need for pooling. This method is quick and easy and results can be obtained within 48 hours after harvesting of cells or tissues. As no special equipment is required, this method can be applied by any laboratory interested in the analysis of DNaseI hypersensitive regions.Open chromatin is a characteristic of genomic loci with regulatory functions. These regions are preferentially digested by DNaseI [1], and the identification of DNaseI hypersensitive sites is frequently used to identify and analyse regulatory regions such as promoters, enhancers and silencers [2,3]. However, currently available methods have significant limitations. A commonly used approach involves Southern blotting, but this is time consuming, usually requires radioactivity and is limited to short stretches of DNA. Several PCR-based methods have been described [4,5], but these do not readily allow multiplexing. Recent
Overexpression of Aromatase Alone is Sufficient for Ovarian Development in Genetically Male Chicken Embryos
Luke S. Lambeth, David M. Cummins, Timothy J. Doran, Andrew H. Sinclair, Craig A. Smith
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0068362
Abstract: Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterised steroidogenic pathway, which is a multi-step process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1) is expressed female-specifically from the time of gonadal sex differentiation. To further explore the role of aromatase in sex determination, we ectopically delivered this enzyme using the retroviral vector RCASBP in ovo. Aromatase overexpression in male chicken embryos induced gonadal sex-reversal characterised by an enlargement of the left gonad and development of ovarian structures such as a thickened outer cortex and medulla with lacunae. In addition, the expression of key male gonad developmental genes (DMRT1, SOX9 and Anti-Müllerian hormone (AMH)) was suppressed, and the distribution of germ cells in sex-reversed males followed the female pattern. The detection of SCP3 protein in late stage sex-reversed male embryonic gonads indicated that these genetically male germ cells had entered meiosis, a process that normally only occurs in female embryonic germ cells. This work shows for the first time that the addition of aromatase into a developing male embryo is sufficient to direct ovarian development, suggesting that male gonads have the complete capacity to develop as ovaries if provided with aromatase.
Development of Retroviral Vectors for Tissue-Restricted Expression in Chicken Embryonic Gonads
Luke S. Lambeth, Thomas Ohnesorg, David M. Cummins, Andrew H. Sinclair, Craig A. Smith
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0101811
Abstract: The chicken embryo has long been a useful model organism for studying development, including sex determination and gonadal differentiation. However, manipulating gene expression specifically in the embryonic avian gonad has been difficult. The viral vector RCASBP can be readily used for embryo-wide transgene expression; however global mis-expression using this method can cause deleterious off-target effects and embryo-lethality. In an attempt to develop vectors for the over-expression of sequences in chicken embryonic urogenital tissues, the viral vector RCANBP was engineered to contain predicted promoter sequences of gonadal-expressed genes. Several promoters were analysed and it was found that although the SF1 promoter produced a tissue-restricted expression pattern that was highest in the mesonephros and liver, it was also higher in the gonads compared to the rest of the body. The location of EGFP expression from the SF1 promoter overlapped with several key gonad-expressed sex development genes; however expression was generally low-level and was not seen in all gonadal cells. To further validate this sequence the key testis determinant DMRT1 was over-expressed in female embryos, which due to insufficient levels had no effect on gonad development. The female gene aromatase was then over-expressed in male embryos, which disrupted the testis pathway as demonstrated by a reduction in AMH protein. Taken together, although these data showed that the SF1 promoter can be used for functional studies in ovo, a stronger promoter sequence would likely be required for the functional analysis of gonad genes that require high-level expression.
Correlations between concentrations of plasma homocysteine and phospholipid fatty acids in healthy male Australian
Duo Li,Andrew J. Sinclair
Songklanakarin Journal of Science and Technology , 2006,
Abstract: An increased plasma homocysteine level has been claimed as an independent risk factor, and increased levels of tissue membrane omega-3 polyunsaturated fatty acid (PUFA) has been suggested to have a protective effect on cardiovascular diseases. However, there is no data on the relationship between the concentrations of plasma homocysteine and phospholipid fatty acid. The aim of this study was to investigate the relationship of plasma homocysteine with phospholipid fatty acids in healthy male Australian. One hundred and thirty six healthy male subjects aged 20-55 years were recruited from Melbourne metropolitan area. Each volunteer completed a semi-quantitative food frequency questionnaire and gave a blood sample. Plasma homocysteine concentrations were determined using HPLC, and plasma phospholipid fatty acids were determined with standard methods. Plasma homocysteine concentration was significantly negatively correlated with plasma phospholipid concentration of PUFA 20:5n-3 (r = -0.226, P = 0.009), 22:5n-3 (r = -0.182, P = 0.036), 22:6n-3 (r = -0.286, P = 0.001), total n-3 (r = -0.270, P = 0.002) and ratio n-3/n-6 PUFA (r = -0.265, P = 0.002), and significantly positively correlated with 20:4n-6 (r = 0.180, P = 0.037). Present results showed that increased concentration of n-3 PUFA in tissues was negatively correlated with plasma homocysteine levels.
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 , 2011, DOI: 10.1371/journal.pone.0020736
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 p27KIP1, p15INK4B, 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.
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 , 2013, DOI: 10.1371/journal.pone.0054606
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.
Impact of Foreign direct investment on the development and emerging economies: The case of China
Robert H. Sinclair(MSc#41;
School of Doctoral Studies Journal , 2010,
Abstract: This paper describes the impact of Foreign Direct Investment (FDI) inflows on the development of the economy of emerging markets. The focus will be on the performance of Chinese locally owned firms. Some of the topics covered in this paper include theories of the firm, globalization and economic development theories. This paper will examine many aspects of China's economy, including economic and market reform policies, labor standards, capital market integration, foreign capital participation, productivity, risks and their correlated effects, and the role they play in shaping the level of economic development, and market acceptance among investors.
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