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  • Gonadal defects in Cited2-mutant mice indicate a role for SF1 in both testis and ovary differentiation.

    7 November 2018

    Sex determination is regulated by a molecular antagonism between testis- and ovary-determining pathways in the supporting cell lineage of the gonadal primordia. Genes important for maintaining this lineage play critical roles in early gonadal development, but their influence on testis and ovary differentiation is unclear due to the severity of loss-of-function phenotypes. The transcription factor SF1 (Nr5a1/Ad4BP) is one such factor, required for establishing the supporting cell lineage, and for propagating the male pathway. In the gonad, Sf1 expression is enhanced by the transcriptional co-factor Cited2. We have used the reduced levels of Sf1 expression in Cited2(-/-) mice as a hypomorphic model to gain insight into the sex-specific roles of SF1 function in gonadal development. In XY mutant mice, we found that testis development was delayed in Cited2(-/-) gonads, and that testis structure was permanently disrupted. In XX Cited2(-/-) gonads, ectopic cell migration was observed which correlated with a transient upregulation of Fgf9, and a delay in Wnt4 then Foxl2 expression. These data suggest a novel role for SF1 in promoting ovarian development in addition to its roles in testis differentiation.

  • Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells.

    7 November 2018

    In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2, and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo. We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2, which impairs HIF signaling and endothelial proangiogenic function.

  • The role of hypoxia in development of the Mammalian embryo.

    7 November 2018

    Hypoxia inducible factor (HIF) is a transcription factor that acts in low-oxygen conditions. The cellular response to HIF activation is transcriptional upregulation of a large group of genes. Some target genes promote anaerobic metabolism to reduce oxygen consumption, while others "alleviate" hypoxia by acting non-cell-autonomously to extend and modify the surrounding vasculature. Although hypoxia is often thought of as being a pathological phenomenon, the mammalian embryo in fact develops in a low-oxygen environment, and in this context HIF has additional responsibilities. This review describes how low oxygen and HIF affect gene expression, cell behavior, and ultimately morphogenesis of the embryo and placenta.

  • Characterizing embryonic gene expression patterns in the mouse using nonredundant sequence-based selection.

    7 November 2018

    This article investigates the expression patterns of 160 genes that are expressed during early mouse development. The cDNAs were isolated from 7.5 d postcoitum (dpc) endoderm, a region that comprises visceral endoderm (VE), definitive endoderm, and the node-tissues that are required for the initial steps of axial specification and tissue patterning in the mouse. To avoid examining the same gene more than once, and to exclude potentially ubiquitously expressed housekeeping genes, cDNA sequence was derived from 1978 clones of the Endoderm library. These yielded 1440 distinct cDNAs, of which 123 proved to be novel in the mouse. In situ hybridization analysis was carried out on 160 of the cDNAs, and of these, 29 (18%) proved to have restricted expression patterns.

  • Cloning of mouse Cited4, a member of the CITED family p300/CBP-binding transcriptional coactivators: induced expression in mammary epithelial cells.

    7 November 2018

    The CITED family proteins bind to CBP/p300 transcriptional integrators through their conserved C-terminal acidic domain and function as coactivators. The 21-kDa mouse Cited4 protein, a novel member of the CITED family, interacted with CBP/p300 as well as isoforms of the TFAP2 transcription factor, coactivating TFAP2-dependent transcription. The cited4 gene consisted of only a single exon located on chromosome 4 at 56.5-56.8 cM flanked by marker genes kcnq4 and scml1. Expression of Cited4 protein was strong and selective in embryonic hematopoietic tissues and endothelial cells. In adult animals, Cited4 showed strong milk cycle-dependent induction in pregnant and lactating mammary epithelial cells. Strong induction of Cited4 expression was also observed in SCp2 mouse mammary epithelial cells during their prolactin-dependent in vitro differentiation. These results implied possible roles for Cited4 in regulation of gene expression during development and differentiation of blood cells, endothelial cells, and mammary epithelial cells.

  • Cooperation between somatic Ikaros and Notch1 mutations at the inception of T-ALL.

    7 November 2018

    To understand the interactions between Notch1 and Ikaros in the evolution of T cell acute lymphoblastic leukemia (T-ALL), we traced the evolution of T-ALL in mice with an inherited Ikaros mutation, Ikzf1(Plstc) which inactivates DNA binding. DNA-binding Ikaros repressed Notch1 response in transfected cell lines and in CD4(+)8(+) (DP) thymocytes from young pre-leukemic Ikzf1(Plstc) heterozygous mice. In DP thymocytes, a 50-1000 fold escalation in mRNA for Notch1 target genes Hes1 and Dtx1 preceded thymic lymphoma or leukemia and was closely correlated with the first detectable differentiation abnormalities, loss of heterozygosity (LOH) eliminating wild-type Ikzf1, and multiple missense and truncating Notch1 mutations. These findings illuminate the early stages of leukemogenesis by demonstrating progressive exaggeration of Notch1 responsiveness at the DP thymocyte stage brought about by multiple mutations acting in concert upon the Notch1 pathway.

  • Oliver Group

    10 July 2016

    Investigating novel gene function in neurodegeneration and behaviour

  • Parekh Group

    16 September 2013

    Intracellular calcium signalling in health and disease

  • Parker Group

    10 July 2016

    Neural systems and circuits for visual perception

  • Paterson Group

    10 July 2016

    Gene Transfer of Nitric Oxide Synthase into Cardiac Nerves Modulates Neurotransmission

  • Riley Group

    10 July 2016

  • Robbins Group

    21 January 2019

    Human systems physiology: Respiratory, cardiovascular and metabolic function in response to stresses such as exercise and hypoxia

  • Smart Group

    10 July 2016

    Development, homeostasis and regeneration of the cardiovascular system

  • Srinivas Group

    10 July 2016

    Patterning and morphogenesis of the early mammalian embryo

  • Swietach Group

    10 July 2016

    Acid handling and signalling in the heart and in cancer

  • Szele Group

    10 July 2016

    We study postnatal and adult mammalian brain stem cells to uncover fundamental developmental mechanisms and disease pathogenesis.