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  • Molecular diagnosis of vertebral segmentation disorders in humans.

    7 November 2018

    BACKGROUND: Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement and functional distress. OBJECTIVE: To provide an overview of the current understanding of vertebral malformations, at both the clinical level and the molecular level, and factors that contribute to their occurrence. METHODS: The literature related to the following was reviewed: recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformations; and complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and non-syndromic congenital vertebral malformations. RESULTS/CONCLUSION: Expert opinions extend to discussion of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families.

  • Dll3 and Notch1 genetic interactions model axial segmental and craniofacial malformations of human birth defects.

    7 November 2018

    Mutations in the Notch1 receptor and delta-like 3 (Dll3) ligand cause global disruptions in axial segmental patterning. Genetic interactions between members of the notch pathway have previously been shown to cause patterning defects not observed in single gene disruptions. We examined Dll3-Notch1 compound mouse mutants to screen for potential gene interactions. While mice heterozygous at either locus appeared normal, 30% of Dll3-Notch1 double heterozygous animals exhibited localized, segmental anomalies similar to human congenital vertebral defects. Unexpectedly, double heterozygous mice also displayed statistically significant reduction of mandibular height and decreased length of the [corrected] maxillary hard palate. Examination of somite-stage embryos and perinatal anatomy and histology did not reveal any organ defects, so we used microarray-based analysis of Dll3 and Notch1 mutant embryos to identify gene targets that may be involved in notch-regulated segmental or craniofacial development. Thus, Dll3-Notch1 double heterozygous mice model human congenital scoliosis and craniofacial disorders.

  • A radiation hybrid transcript map of the mouse genome.

    7 November 2018

    Expressed-sequence tag (EST) maps are an adjunct to sequence-based analytical methods of gene detection and localization for those species for which such data are available, and provide anchors for high-density homology and orthology mapping in species for which large-scale sequencing has yet to be done. Species for which radiation hybrid-based transcript maps have been established include human, rat, mouse, dog, cat and zebrafish. We have established a comprehensive first-generation-placement radiation hybrid map of the mouse consisting of 5,904 mapped markers (3,993 ESTs and 1,911 sequence-tagged sites (STSs)). The mapped ESTs, which often originate from small-EST clusters, are enriched for genes expressed during early mouse embryogenesis and are probably different from those localized in humans. We have confirmed by in situ hybridization that even singleton ESTs, which are usually not retained for mapping studies, may represent bona fide transcribed sequences. Our studies on mouse chromosomes 12 and 14 orthologous to human chromosome 14 show the power of our radiation hybrid map as a predictive tool for orthology mapping in humans.

  • Cited2 is required for the proper formation of the hyaloid vasculature and for lens morphogenesis.

    7 November 2018

    Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2(-/-) developing eyes, a feature reminiscent of Peters' anomaly, which can be rescued by increased Pax6 gene dosage in Cited2(-/-) embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1alpha) in Cited2(-/-) lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2: one upstream of, or together with, Pax6 in lens morphogenesis; and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters' anomaly and ocular hypervascularity.

  • A cell autonomous role for the Notch ligand Delta-like 3 in αβ T-cell development.

    7 November 2018

    Notch signalling is critical to help direct T-cell lineage commitment in early T-cell progenitors and in the development of αβ T-cells. Epithelial and stromal cell populations in the thymus express the Notch DSL (Delta, Serrate and Lag2)ligands Delta-like 1 (Dll1), Delta-like 4 (Dll4), Jagged 1 and Jagged 2, and induce Notch signalling in thymocytes that express the Notch receptor. At present there is nothing known about the role of the Delta-like 3 (Dll3) ligand in the immune system. Here we describe a novel cell autonomous role for Dll3 in αβ T-cell development. We show that Dll3 cannot activate Notch when expressed in trans but like other Notch ligands it can inhibit Notch signalling when expressed in cis with the receptor. The loss of Dll3 leads to an increase in Hes5 expression in double positive thymocytes and their increased production of mature CD4(+) and CD8(+) T cells. Studies using competitive irradiation chimeras proved that Dll3 acts in a cell autonomous manner to regulate positive selection but not negative selection of autoreactive T cells. Our results indicate that Dll3 has a unique function during T-cell development that is distinct from the role played by the other DSL ligands of Notch and is in keeping with other recent studies indicating that Dll1 and Dll3 ligands have non-overlapping roles during embryonic development.

  • The role of Notch in patterning the human vertebral column.

    7 November 2018

    The components of the Notch signaling pathway and the mechanics of signal transduction have largely been established in Drosophila. Although essential for many developmental processes in invertebrates and vertebrates, this review focuses on Notch signaling in the vertebrate-specific process of somitogenesis. More specifically it describes that mutations in genes encoding Notch pathway components (DLL3, MESP2, LFNG and HES7) cause severe congenital vertebral defects in humans. Importantly, this review highlights studies demonstrating that Dll3 is unique amongst DSL ligands acting as an inhibitor and not an activator of Notch signaling.

  • Edd, the murine hyperplastic disc gene, is essential for yolk sac vascularization and chorioallantoic fusion.

    7 November 2018

    EDD is the mammalian ortholog of the Drosophila melanogaster hyperplastic disc gene (hyd), which is critical for cell proliferation and differentiation in flies through regulation of hedgehog and decapentaplegic signaling. Amplification and overexpression of EDD occurs frequently in several cancers, including those of the breast and ovary, and truncating mutations of EDD are also observed in gastric and colon cancer with microsatellite instability. EDD has E3 ubiquitin ligase activity, is involved in regulation of the DNA damage response, and may control hedgehog signaling, but a definitive biological role has yet to be established. To investigate the role of Edd in vivo, gene targeting was used to generate Edd knockout (Edd(Delta/Delta)) mice. While heterozygous mice had normal development and fertility, no viable Edd-deficient embryos were observed beyond E10.5, with delayed growth and development evident from E8.5 onward. Failed yolk sac and allantoic vascular development, along with defective chorioallantoic fusion, were the primary effects of Edd deficiency. These extraembryonic defects presumably compromised fetal-maternal circulation and hence efficient exchange of nutrients and oxygen between the embryo and maternal environment, leading to a general failure of embryonic cell proliferation and widespread apoptosis. Hence, Edd has an essential role in extraembryonic development.

  • Taylor Group

    10 July 2016

    Axon Growth and Guidance in the Developing and Regenerating Central Nervous System

  • Tyler Group

    10 July 2016

    Development and Application of Cardiac Magnetic Resonance Imaging and Spectroscopy

  • Waddell Group

    10 July 2016

    Memory, motivation and individuality

  • Sparrow Group

    22 October 2015

    Investigating the Genetic and Environmental Causes of Congenital Heart Disease

  • Hens Group

    16 September 2013

  • Patton Group

    28 April 2014

    Nanodiamond as a sensor for biologically generated electric and magnetic fields

  • Garcia-Moreno Group

    19 December 2013

    Forebrain Evolution Research laboratory

  • Zifarelli Group

    5 February 2015

    CLC chloride channels and transporters

  • Packer Group

    21 May 2018