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  • A tyrosine-rich domain within homeodomain transcription factor Nkx2-5 is an essential element in the early cardiac transcriptional regulatory machinery.

    7 November 2018

    Homeodomain factor Nkx2-5 is a central component of the transcription factor network that guides cardiac development; in humans, mutations in NKX2.5 lead to congenital heart disease (CHD). We have genetically defined a novel conserved tyrosine-rich domain (YRD) within Nkx2-5 that has co-evolved with its homeodomain. Mutation of the YRD did not affect DNA binding and only slightly diminished transcriptional activity of Nkx2-5 in a context-specific manner in vitro. However, the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo. Furthermore, heterozygous mutation of all nine tyrosines to alanine created an allele with a strong dominant-negative-like activity in vivo: ES cell<-->embryo chimaeras bearing the heterozygous mutation died before term with cardiac malformations similar to the more severe anomalies seen in NKX2.5 mutant families. These studies suggest a functional interdependence between the NK2 class homeodomain and YRD in cardiac development and evolution, and establish a new model for analysis of Nkx2-5 function in CHD.

  • Cited2 is required both for heart morphogenesis and establishment of the left-right axis in mouse development.

    7 November 2018

    Establishment of the left-right axis is a fundamental process of vertebrate embryogenesis. Failure to develop left-right asymmetry leads to incorrect positioning and morphogenesis of numerous internal organs, and is proposed to underlie the etiology of several common cardiac malformations. The transcriptional modulator Cited2 is essential for embryonic development: Cited2-null embryos die during gestation with profound developmental abnormalities, including cardiac malformations, exencephaly and adrenal agenesis. Cited2 is also required for normal establishment of the left-right axis; we demonstrate that abnormal heart looping and right atrial and pulmonary isomerism are consistent features of the left-right-patterning defect. We show by gene expression analysis that Cited2 acts upstream of Nodal, Lefty2 and Pitx2 in the lateral mesoderm, and of Lefty1 in the presumptive floor plate. Although abnormal left-right patterning has a major impact on the cardiac phenotype in Cited2-null embryos, laterality defects are only observed in a proportion of these embryos. We have therefore used a combination of high-resolution imaging and three-dimensional (3D) modeling to systematically document the full spectrum of Cited2-associated cardiac defects. Previous studies have focused on the role of Cited2 in cardiac neural crest cell development, as Cited2 can bind the transcription factor Tfap2, and thus affect the expression of Erbb3 in neural crest cells. However, we have identified Cited2-associated cardiac defects that cannot be explained by laterality or neural crest abnormalities. In particular, muscular ventricular septal defects and reduced cell density in the atrioventricular (AV) endocardial cushions are evident in Cited2-null embryos. As we found that Cited2 expression tightly correlated with these sites, we believe that Cited2 plays a direct role in development of the AV canal and cardiac septa. We therefore propose that, in addition to the previously described reduction of cardiac neural crest cells, two other distinct mechanisms contribute to the spectrum of complex cardiac defects in Cited2-null mice; disruption of normal left-right patterning and direct loss of Cited2 expression in cardiac tissues.

  • Msg1 and Mrg1, founding members of a gene family, show distinct patterns of gene expression during mouse embryogenesis.

    7 November 2018

    Msg1 and Mrg1 are founding members of a gene family which exhibit distinct patterns of gene expression during mouse embryogenesis. Sequence analysis reveals that these genes are unlike any other gene identified to date, but they share two near-identical sequence domains. The Msg1 and Mrg1 expression profiles during early development are distinct from each other. Msg1 is predominantly expressed in nascent mesoderm, the heart tube, limb bud and sclerotome. Intriguingly, Msg1 expression is restricted, within these developing mesodermal sites, to posterior domains. Mrg1 is expressed prior to gastrulation in the anterior visceral endoderm. Expression is maintained in the endoderm once gastrulation has begun and commences in the rostralmost embryonic mesoderm which underlies the anterior visceral endoderm. Mrg1 expression persists in this rostral mesoderm as it is translocated caudalwards during the invagination of the foregut and the formation of the heart. Later Mrg1 expression predominates in the septum transversum caudal to the heart. This expression pattern suggests that the septum transversum originates from the rostralmost embryonic mesoderm which first expressed Mrg1 at the late primitive streak stage.

  • Mutation of the fucose-specific beta1,3 N-acetylglucosaminyltransferase LFNG results in abnormal formation of the spine.

    7 November 2018

    Notch signaling is an evolutionarily conserved mechanism that determines cell fate in a variety of contexts during development. This is achieved through different modes of action that are context dependent. One mode involves boundary formation between two groups of cells. With this mode of action, Notch signaling is central to vertebrate evolution as it drives the segmentation of paraxial mesoderm in the formation of somites, which are the precursors of the vertebra. In this case, boundary formation facilitates a mesenchymal to epithelial transition, leading to the creation of a somite. In addition, the boundary establishes a signaling center that patterns the somite, a feature that directly impacts on vertebral column formation. Studies in Xenopus, zebrafish, chicken and mouse have established the importance of Notch signaling in somitogenesis, and indeed in mouse how perturbations in somitogenesis affect vertebral column formation. Spondylocostal dysostosis is a congenital disorder characterized by formation of abnormal vertebrae. Here, mutation in Notch pathway genes demonstrates that Notch signaling is also required for normal somite formation and vertebral column development in humans; of particular interest here is mutation of the LUNATIC FRINGE (LFNG) gene, which causes SCD type 3. LUNATIC FRINGE encodes for a fucose-specific beta1,3-N-acetylglucosaminyltransferase, which modifies Notch receptors and alters Notch signaling activity. This review will focus on Notch glycolsylation, and the role of LUNATIC FRINGE in somite formation and vertebral column development in mice and humans.

  • Combinatorial signaling in the heart orchestrates cardiac induction, lineage specification and chamber formation.

    7 November 2018

    The complexity of mammalian cardiogenesis is compounded, as the heart must function in the embryo whilst it is still being formed. Great advances have been made recently as additional cardiac progenitor cell populations have been identified. The induction and maintenance of these progenitors, and their deployment to the developing heart relies on combinatorial molecular signalling, a feature also of cardiac chamber formation. Many forms of congenital heart disease in humans are likely to arise from defects in the early stages of heart development; therefore it is important to understand the molecular pathways that underlie some of the key events that shape the heart during the early stages of it development.

  • Notch1 endocytosis is induced by ligand and is required for signal transduction.

    7 November 2018

    The Notch signalling pathway is widely utilised during embryogenesis in situations where cell-cell interactions are important for cell fate specification and differentiation. DSL ligand endocytosis into the ligand-expressing cell is an important aspect of Notch signalling because it is thought to supply the force needed to separate the Notch heterodimer to initiate signal transduction. A functional role for receptor endocytosis during Notch signal transduction is more controversial. Here we have used live-cell imaging to examine trafficking of the Notch1 receptor in response to ligand binding. Contact with cells expressing ligands induced internalisation and intracellular trafficking of Notch1. Notch1 endocytosis was accompanied by transendocytosis of ligand into the Notch1-expressing signal-receiving cell. Ligand caused Notch1 endocytosis into SARA-positive endosomes in a manner dependent on clathrin and dynamin function. Moreover, inhibition of endocytosis in the receptor-expressing cell impaired ligand-induced Notch1 signalling. Our findings resolve conflicting observations from mammalian and Drosophila studies by demonstrating that ligand-dependent activation of Notch1 signalling requires receptor endocytosis. Endocytosis of Notch1 may provide a force on the ligand:receptor complex that is important for potent signal transduction.

  • Progress in the understanding of the genetic etiology of vertebral segmentation disorders in humans.

    7 November 2018

    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. This review explores (1) 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; (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation; and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and nonsyndromic congenital vertebral malformation. Discussion includes exploration 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.

  • Riley Group

    10 July 2016

  • Robbins Group

    11 January 2019

    Human physiology: Effects of hypoxia and exercise on respiratory, cardiovascular and metabolic function

  • 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

  • Stein Group

    16 September 2013

    Visuomotor control in movement disorders and developmental dyslexia

  • 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.

  • 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