Institute for Genetics and Molecular Medicine

Edinburgh, United Kingdom

Institute for Genetics and Molecular Medicine

Edinburgh, United Kingdom
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News Article | May 18, 2017
Site: www.eurekalert.org

A genetic mutation that contributes to sight loss in children has been identified by scientists. The mutation was identified in patients with a disease known as ocular coloboma, which causes part of the eye to be missing at birth. The findings shed light on its causes and help to explain how genes contribute to development of the eye, researchers say. Ocular coloboma accounts for up to 10 per cent of all childhood blindness. It can cause a distinctive keyhole-shaped pupil as it commonly results in a missing segment in the iris, the coloured part of the eye. Few genetic causes have so far been found to explain the cause of coloboma. The research team -- lead by the University of Edinburgh -- worked with 12 families, studying the DNA of children with coloboma and their unaffected parents. Using state-of-the-art genetic screening -- known as whole exome sequencing -- the scientists revealed mutations in 10 genes, three of which were linked to activity of one molecule. The molecule -- known as actin -- is important to a number of vital cell functions, including maintenance of the cytoskeleton, which defines cell shape and structure. Targeted gene sequencing was then carried out on a further 380 people with coloboma. This showed that one of the mutations -- a specific alteration in the gene ACTG1 -- recurred across a number of those tested. The scientists edited this ACTG1 mutation into a line of mice using cutting-edge CRISPR/Cas9 gene-editing technology, and found that it had severe effects on the function of actin. The newly-identified mutations are thought to affect how actin binds to other proteins and on actin stability, which could severely affect development of the eye in the womb, scientists say. Dr Joe Rainger, Fight for Sight Early Career Investigator Fellow at the University of Edinburgh's Roslin Institute and Royal (Dick) School of Veterinary Studies, said: "Coloboma can have profound effects on visual ability, but it is very variable and therefore likely to be caused by a number of genes. "Our work adds knowledge to our understanding of its onset as well as the importance of actin to eye development." The work -- published in the journal Human Mutation -- was carried out at the University of Edinburgh's Institute for Genetics and Molecular Medicine and the Roslin Institute. The study was funded by eye research charity Fight for Sight. George McNamara, Director of Research, Policy and Innovation at Fight for Sight, said: "Sight loss due to coloboma in children can be devastating. "Very little is known about the cause, and this study has helped advance our knowledge about the development of the eye. "As this work progresses, we have the opportunity to come closer to understanding the causes of childhood sight loss."


Vermeren S.,Queens Medical Research Institute | Miles K.,Queens Medical Research Institute | Chu J.Y.,Queens Medical Research Institute | Salter D.,Institute for Genetics and Molecular Medicine | And 2 more authors.
Journal of Immunology | Year: 2016

Neutrophils act as a first line of defense against bacterial and fungal infections, but they are also important effectors of acute and chronic inflammation. Genome-wide association studies have established that the gene encoding the protein tyrosine phosphatase nonreceptor 22 (PTPN22) makes an important contribution to susceptibility to autoimmune disease, notably rheumatoid arthritis. Although PTPN22 is most highly expressed in neutrophils, its function in these cells remains poorly characterized. We show in this article that neutrophil effector functions, including adhesion, production of reactive oxygen species, and degranulation induced by immobilized immune complexes, were reduced in Ptpn22-/- neutrophils. Tyrosine phosphorylation of Lyn and Syk was altered in Ptpn22-/- neutrophils. On stimulation with immobilized immune complexes, Ptpn22-/- neutrophils manifested reduced activation of key signaling intermediates. Ptpn22-/- mice were protected from immune complex-mediated arthritis, induced by the transfer of arthritogenic serum. In contrast, in vivo neutrophil recruitment following thioglycollate-induced peritonitis and in vitro chemotaxis were not affected by lack of PTPN22. Our data suggest an important role for PTPN22-dependent dephosphorylation events, which are required to enable full FcγR-induced activation, pointing to an important role for this molecule in neutrophil function. Copyright © 2016 by The American Association of Immunologists, Inc.


Martinez-Estrada O.M.,Institute for Genetics and Molecular Medicine | Lettice L.A.,Institute for Genetics and Molecular Medicine | Essafi A.,Institute for Genetics and Molecular Medicine | Guadix J.A.,University of Malaga | And 10 more authors.
Nature Genetics | Year: 2010

The epicardial epithelial-mesenchymal transition (EMT) is hypothesized to generate cardiovascular progenitor cells that differentiate into various cell types, including coronary smooth muscle and endothelial cells, perivascular and cardiac interstitial fibroblasts and cardiomyocytes. Here we show that an epicardial-specific knockout of the gene encoding Wilms' tumor-1 (Wt1) leads to a reduction in mesenchymal progenitor cells and their derivatives. We show that Wt1 is essential for repression of the epithelial phenotype in epicardial cells and during embryonic stem cell differentiation through direct transcriptional regulation of the genes encoding Snail (Snai1) and E-cadherin (Cdh1), two of the major mediators of EMT. Some mesodermal lineages do not form in Wt1-null embryoid bodies, but this effect is rescued by the expression of Snai1, underscoring the importance of EMT in generating these differentiated cells. These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT will shed light on the pathogenesis of heart diseases and may help the development of cell-based therapies. © 2010 Nature America, Inc. All rights reserved.


Long K.,University of Edinburgh | Moss L.,University of Edinburgh | Laursen L.,University of Aarhus | Boulter L.,Institute for Genetics and Molecular Medicine | Ffrench-Constant C.,University of Edinburgh
Nature Communications | Year: 2016

Development of the cerebral cortex requires regulation of proliferation and differentiation of neural stem cells and a diverse range of progenitors. Recent work suggests a role for extracellular matrix (ECM) and the major family of ECM receptors, the integrins. Here we show that enhancing integrin beta-1 signalling, by expressing a constitutively active integrin beta-1 (CA∗β1) in the embryonic chick mesencephalon, enhances neurogenesis and increases the number of mitotic cells dividing away from the ventricular surface, analogous to sub-apical progenitors in mouse. Only non-integrin-expressing neighbouring cells (lacking CA∗β1) contributed to the increased neurogenesis. Transcriptome analysis reveals upregulation of Wnt7a within the CA∗β1 cells and upregulation of the ECM protein Decorin in the neighbouring non-expressing cells. Experiments using inhibitors in explant models and genetic knock-downs in vivo reveal an integrin-Wnt7a-Decorin pathway that promotes proliferation and differentiation of neuroepithelial cells, and identify Decorin as a novel neurogenic factor in the central nervous system.


PubMed | University of Aarhus, Institute for Genetics and Molecular Medicine and University of Edinburgh
Type: | Journal: Nature communications | Year: 2016

Development of the cerebral cortex requires regulation of proliferation and differentiation of neural stem cells and a diverse range of progenitors. Recent work suggests a role for extracellular matrix (ECM) and the major family of ECM receptors, the integrins. Here we show that enhancing integrin beta-1 signalling, by expressing a constitutively active integrin beta-1 (CA*1) in the embryonic chick mesencephalon, enhances neurogenesis and increases the number of mitotic cells dividing away from the ventricular surface, analogous to sub-apical progenitors in mouse. Only non-integrin-expressing neighbouring cells (lacking CA*1) contributed to the increased neurogenesis. Transcriptome analysis reveals upregulation of Wnt7a within the CA*1 cells and upregulation of the ECM protein Decorin in the neighbouring non-expressing cells. Experiments using inhibitors in explant models and genetic knock-downs in vivo reveal an integrin-Wnt7a-Decorin pathway that promotes proliferation and differentiation of neuroepithelial cells, and identify Decorin as a novel neurogenic factor in the central nervous system.


Dolle L.,Vrije Universiteit Brussel | Theise N.D.,Yeshiva University | Schmelzer E.,McGowan Institute for Regenerative Medicine | Boulter L.,Institute for Genetics and Molecular Medicine | And 2 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2015

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is frequently and highly expressed on carcinomas, tumor-initiating cells, selected tissue progenitors, and embryonic and adult stem cells. During liver development, EpCAM demonstrates a dynamic expression, since it can be detected in fetal liver, including cells of the parenchyma, whereas mature hepatocytes are devoid of EpCAM. Liver regeneration is associated with a population of EpCAM-positive cells within ductular reactions, which gradually lose the expression of EpCAM along with maturation into hepatocytes. EpCAM can be switched on and off through a wide panel of strategies to fine-tune EpCAM-dependent functional and differentiative traits. EpCAM-associated functions relate to cell–cell adhesion, proliferation, maintenance of a pluripotent state, regulation of differentiation, migration, and invasion. These functions can be conferred by the full-length protein and/or EpCAM-derived fragments, which are generated upon regulated intramembrane proteolysis. Control by EpCAM therefore not only depends on the presence of full-length EpCAM at cellular membranes but also on varying rates of the formation of EpCAM-derived fragments that have their own regulatory properties and on changes in the association of EpCAM with interaction partners. Thus spatiotemporal localization of EpCAM in immature liver progenitors, transit-amplifying cells, and mature liver cells will decisively impact the regulation of EpCAM functions and might be one of the triggers that contributes to the adaptive processes in stem/progenitor cell lineages. This review will summarize EpCAM-related molecular events and how they relate to hepatobiliary differentiation and regeneration. © the American Physiological Society.


Dolle L.,Vrije Universiteit Brussel | Boulter L.,Institute for Genetics and Molecular Medicine | Leclercq I.A.,Catholic University of Louvain | van Grunsven L.A.,Vrije Universiteit Brussel
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2015

High aldehydedehydrogenase (ALDH) activity is a feature of stem cells from normal and cancerous tissues and a reliable universal marker used to isolate them. There are numerous ALDH isoforms with preferred substrate specificity variably expressed depending on tissue, cell type, and organelle and cell status. On the other hand, a given substrate may be metabolized by several enzyme isoforms. Currently ALDH activity is evidenced by using Aldefluor, a fluorescent substrate likely to be metabolized by numerous ALDH isoforms. Therefore, isolation techniques based on ALDH activity detection select a heterogeneous population of stem or progenitor cells. Despite active research in the field, the precise role(s) of different ALDH isoforms in stem cells remains enigmatic. Understanding the metabolic role of different ALDH isoform in the control of stem cell phenotype and cell fate during development, tissue homeostasis, or repair, as well as carcinogenesis, should open perspectives to significant discoveries in tissue biology. In this perspective, novel ALDH substrates are being developed. Here we describe how new substrates could be instrumental for better isolation of cell population with stemness potential and for defining hierarchy of cell populations in tissue. Finally, we speculate on other potential applications. © 2015 the American Physiological Society.


PubMed | Institute for Genetics and Molecular Medicine, Queens Medical Research Institute and University of Edinburgh
Type: Journal Article | Journal: Journal of immunology (Baltimore, Md. : 1950) | Year: 2016

Neutrophils act as a first line of defense against bacterial and fungal infections, but they are also important effectors of acute and chronic inflammation. Genome-wide association studies have established that the gene encoding the protein tyrosine phosphatase nonreceptor 22 (PTPN22) makes an important contribution to susceptibility to autoimmune disease, notably rheumatoid arthritis. Although PTPN22 is most highly expressed in neutrophils, its function in these cells remains poorly characterized. We show in this article that neutrophil effector functions, including adhesion, production of reactive oxygen species, and degranulation induced by immobilized immune complexes, were reduced in Ptpn22


PubMed | Institute for Genetics and Molecular Medicine, Catholic University of Louvain and Vrije Universiteit Brussel
Type: Journal Article | Journal: American journal of physiology. Gastrointestinal and liver physiology | Year: 2015

High aldehyde dehydrogenase (ALDH) activity is a feature of stem cells from normal and cancerous tissues and a reliable universal marker used to isolate them. There are numerous ALDH isoforms with preferred substrate specificity variably expressed depending on tissue, cell type, and organelle and cell status. On the other hand, a given substrate may be metabolized by several enzyme isoforms. Currently ALDH activity is evidenced by using Aldefluor, a fluorescent substrate likely to be metabolized by numerous ALDH isoforms. Therefore, isolation techniques based on ALDH activity detection select a heterogeneous population of stem or progenitor cells. Despite active research in the field, the precise role(s) of different ALDH isoforms in stem cells remains enigmatic. Understanding the metabolic role of different ALDH isoform in the control of stem cell phenotype and cell fate during development, tissue homeostasis, or repair, as well as carcinogenesis, should open perspectives to significant discoveries in tissue biology. In this perspective, novel ALDH substrates are being developed. Here we describe how new substrates could be instrumental for better isolation of cell population with stemness potential and for defining hierarchy of cell populations in tissue. Finally, we speculate on other potential applications.

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