The Experts below are selected from a list of 441 Experts worldwide ranked by ideXlab platform
Siegfried Ussar - One of the best experts on this subject based on the ideXlab platform.
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kindlin 1 controls wnt and tgf beta availability to regulate cutaneous stem cell proliferation
Nature Medicine, 2014Co-Authors: Emanuel Rognoni, Siegfried Ussar, Moritz Widmaier, Madis Jakobson, Despoina Katsougkri, Ralph T. Böttcher, Daniel B. Rifkin, Raphael Ruppert, Joey Laicheong, John A. McgrathAbstract:Mutations in Kindlin-1 result in Kindler syndrome, which is marked by skin blistering, premature skin aging and increased risk for skin cancer. Reinhard Fassler and his colleagues have developed a new mouse model of the condition, revealing new cellular and molecular mechanistic insight into the pathology of the syndrome. Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting αvβ6 integrin–mediated transforming growth factor-β (TGF-β) activation and inhibiting Wnt–β-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-β–mediated growth-inhibitory signals and Wnt–β-catenin–mediated growth-promoting signals.
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Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation
The American journal of pathology, 2009Co-Authors: Joey Lai-cheong, Siegfried Ussar, Maddy Parsons, Akio Tanaka, Andrew P. South, Sethuraman Gomathy, John B. Mee, Jean-baptiste Barbaroux, Tanasit Techanukul, Noor AlmaaniAbstract:Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. In this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin. In addition, reduced immunolabeling intensity of epidermal cell markers such as β1 and α6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of β4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active β1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kindler syndrome.
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leukocyte adhesion deficiency iii is caused by mutations in kindlin3 affecting integrin activation
Nature Medicine, 2009Co-Authors: Lena Svensson, Alison Mcdowall, Irene Patzak, Kimberley Howarth, Robert W Evans, Siegfried Ussar, Markus Moser, Ayse Metin, Mike Fried, Ian TomlinsonAbstract:Integrins are the major adhesion receptors of leukocytes and platelets. Beta1 and beta2 integrin function on leukocytes is crucial for a successful immune response and the platelet integrin alpha(IIb)beta3 initiates the process of blood clotting through binding fibrinogen. Integrins on circulating cells bind poorly to their ligands but become active after 'inside-out' signaling through other membrane receptors. Subjects with leukocyte adhesion deficiency-1 (LAD-I) do not express beta2 integrins because of mutations in the gene specifying the beta2 subunit, and they suffer recurrent bacterial infections. Mutations affecting alpha(IIb)beta3 integrin cause the bleeding disorder termed Glanzmann's thrombasthenia. Subjects with LAD-III show symptoms of both LAD-I and Glanzmann's thrombasthenia. Their hematopoietically-derived cells express beta1, beta2 and beta3 integrins, but defective inside-out signaling causes immune deficiency and bleeding problems. The LAD-III lesion has been attributed to a C --> A mutation in the gene encoding calcium and diacylglycerol guanine nucleotide exchange factor (CALDAGGEF1; official symbol RASGRP2) specifying the CALDAG-GEF1 protein, but we show that this change is not responsible for the LAD-III disorder. Instead, we identify mutations in the KINDLIN3 (official symbol FERMT3) gene specifying the KINDLIN-3 protein as the cause of LAD-III in Maltese and Turkish subjects. Two independent mutations result in decreased KINDLIN3 messenger RNA levels and loss of protein expression. Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration.
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loss of kindlin 1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction
PLOS Genetics, 2008Co-Authors: Siegfried Ussar, Markus Moser, Moritz Widmaier, Emanuel Rognoni, Christian Harrer, Orsolya Genzelboroviczeny, Reinhard FasslerAbstract:Kindler Syndrome (KS), characterized by transient skin blistering followed by abnormal pigmentation, skin atrophy, and skin cancer, is caused by mutations in the FERMT1 gene. Although a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown. The FERMT1 gene product belongs to a family of focal adhesion proteins (Kindlin-1, -2, -3) that bind several β integrin cytoplasmic domains. Here, we show that deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC. This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response.
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Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction. PLoS Genet
2008Co-Authors: Siegfried Ussar, Markus Moser, Moritz Widmaier, Emanuel Rognoni, See Profile, Orsolya Genzel-boroviczény, Christian HarrerAbstract:Kindler Syndrome (KS), characterized by transient skin blistering followed by abnormal pigmentation, skin atrophy, and skin cancer, is caused by mutations in the FERMT1 gene. Although a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown. The FERMT1 gene product belongs to a family of focal adhesion proteins (Kindlin-1,-2,-3) that bind several b integrin cytoplasmic domains. Here, we show that deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC. This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation
Reinhard Fassler - One of the best experts on this subject based on the ideXlab platform.
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Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous epithelial stem cell proliferation
2016Co-Authors: Emanuel Rognoni, Moritz Widmaier, Madis Jakobson, Despoina Katsougkri, Ralph T. Böttcher, Joey E. Lai-cheong, Daniel B. Rifkin, John A. Mcgrath, Reinhard FasslerAbstract:Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene lead to Kindler Syndrome in man, which is characterized by skin blistering, premature skin ageing and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler Syndrome, and in addition produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through β1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting αvβ6 integrin-mediated TGFβ activation and by inhibiting Wnt-β-catenin signaling through an integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the novel and essential task to control cutaneous epithelial stem cell homeostasis by balancing TGFβ mediated growth inhibitory and Wnt-β-catenin mediated growth-promoting signals
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distinct roles for talin 1 and kindlin 3 in lfa 1 extension and affinity regulation
Blood, 2012Co-Authors: Craig T Lefort, Markus Moser, Reinhard Fassler, Jan Rossaint, Brian G Petrich, Alexander Zarbock, Susan J Monkley, David R Critchley, Mark H Ginsberg, Klaus LeyAbstract:In inflammation, neutrophils and other leukocytes roll along the microvascular endothelium before arresting and transmigrating into inflamed tissues. Arrest requires conformational activation of the integrin lymphocyte function-associated antigen-1 (LFA-1). Mutations of the FERMT3 gene encoding kindlin-3 underlie the human immune deficiency known as leukocyte adhesion deficiency-III. Both kindlin-3 and talin-1, another FERM domain-containing cytoskeletal protein, are required for integrin activation, but their individual roles in the induction of specific integrin conformers are unclear. Here, we induce differential LFA-1 activation in neutrophils through engagement of the selectin ligand P-selectin glycoprotein ligand-1 or the chemokine receptor CXCR2. We find that talin-1 is required for inducing LFA-1 extension, which corresponds to intermediate affinity and induces neutrophil slow rolling, whereas both talin-1 and kindlin-3 are required for induction of the high-affinity conformation of LFA-1 with an open headpiece, which results in neutrophil arrest. In vivo, both slow rolling and arrest are defective in talin-1–deficient neutrophils, whereas only arrest is defective in kindlin-3–deficient neutrophils. We conclude that talin-1 and kindlin-3 serve distinct functions in LFA-1 activation.
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loss of kindlin 1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction
PLOS Genetics, 2008Co-Authors: Siegfried Ussar, Markus Moser, Moritz Widmaier, Emanuel Rognoni, Christian Harrer, Orsolya Genzelboroviczeny, Reinhard FasslerAbstract:Kindler Syndrome (KS), characterized by transient skin blistering followed by abnormal pigmentation, skin atrophy, and skin cancer, is caused by mutations in the FERMT1 gene. Although a few KS patients have been reported to also develop ulcerative colitis (UC), a causal link to the FERMT1 gene mutation is unknown. The FERMT1 gene product belongs to a family of focal adhesion proteins (Kindlin-1, -2, -3) that bind several β integrin cytoplasmic domains. Here, we show that deleting Kindlin-1 in mice gives rise to skin atrophy and an intestinal epithelial dysfunction with similarities to human UC. This intestinal dysfunction results in perinatal lethality and is triggered by defective intestinal epithelial cell integrin activation, leading to detachment of this barrier followed by a destructive inflammatory response.
Fanny Eysert - One of the best experts on this subject based on the ideXlab platform.
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alzheimer s genetic risk factor fermt2 kindlin 2 controls axonal growth and synaptic plasticity in an app dependent manner
Molecular Psychiatry, 2020Co-Authors: Fanny Eysert, Audrey Coulon, Emmanuelle Boscher, Anaїs-camille Vreulx, Amandine Flaig, Tiago Mendes, Sandrine Hughes, Xavier Hanoulle, Benjamin Grenierboley, Florie DemiautteAbstract:Although APP metabolism is being intensively investigated, a large fraction of its modulators is yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimer's disease (AD), as a potential key modulator of axon guidance, a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism, and that FERMT2 underexpression impacts axonal growth, synaptic connectivity, and long-term potentiation in an APP-dependent manner. Last, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3'UTR of FERMT2, induced a downregulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 underexpression in neurons and insight into how this may influence AD pathogenesis.
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alzheimer s genetic risk factor fermt2 kindlin 2 controls axonal growth and synaptic plasticity in an app dependent manner
bioRxiv, 2020Co-Authors: Fanny Eysert, Audrey Coulon, Emmanuelle Boscher, Anaїs-camille Vreulx, Amandine Flaig, Tiago Mendes, Sandrine Hughes, Xavier Hanoulle, Benjamin Grenierboley, Florie DemiautteAbstract:Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimer′s disease (AD), as a potential key modulator of axon guidance; a neuronal process dependent on the APP metabolism regulation. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under-expression impacts axonal growth, synaptic connectivity and long-term potentiation in an APP-dependent manner. Lastly, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3′UTR of FERMT2, induced a down-regulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under-expression in neurons and insight on how this may influence AD pathogenesis.
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genome wide high content sirna screening identifies the alzheimer s genetic risk factor fermt2 as a major modulator of app metabolism
Acta Neuropathologica, 2017Co-Authors: Julien Chapuis, Fanny Eysert, Amandine Flaig, Tiago Mendes, Benjamin Grenierboley, Virginie Pottiez, Gaspard Deloison, Alexandre Vandeputte, Anne Marie Ayral, Shruti DesaiAbstract:Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
Thanos Sioris - One of the best experts on this subject based on the ideXlab platform.
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kindlin 3 FERMT3 is associated with unstable atherosclerotic plaques anti inflammatory type ii macrophages and upregulation of beta 2 integrins in all major arterial beds
Atherosclerosis, 2015Co-Authors: Niku Oksala, Jenita Parssinen, Ilkka Seppala, Norman Klopp, Thomas Illig, Reijo Laaksonen, Mari Levula, Emma Raitoharju, Ivana Kholova, Thanos SiorisAbstract:Abstract Background Kindlins (FERMT) are cytoplasmic proteins required for integrin (ITG) activation, leukocyte transmigration, platelet aggregation and thrombosis. Characterization of kindlins and their association with atherosclerotic plaques in human(s) is lacking. Methods and results Exploratory microarray (MA) was first performed followed by selective quantitative validation of robustly expressed genes with qRT-PCR low-density array (LDA). In LDA, ITGA1 (1.30-fold, p = 0.041) and ITGB3 (1.37-fold, p = 0.036) were upregulated in whole blood samples of patients with coronary artery disease (CAD) compared to healthy controls. In arterial plaques, both robustly expressed transcript variants of FERMT3 (MA: 5.90- and 3.4-fold; LDA: 3.99-fold, p Conclusions Kindlin-3 (FERMT3) is upregulated in atherosclerotic, especially unstable plaques, mainly in cells of monocytic origin and of M2 type. Simultaneous upregulation of ITGB2 suggests a synergistic effect on leukocyte adherence and transmigration into the vessel wall.
Florie Demiautte - One of the best experts on this subject based on the ideXlab platform.
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alzheimer s genetic risk factor fermt2 kindlin 2 controls axonal growth and synaptic plasticity in an app dependent manner
Molecular Psychiatry, 2020Co-Authors: Fanny Eysert, Audrey Coulon, Emmanuelle Boscher, Anaїs-camille Vreulx, Amandine Flaig, Tiago Mendes, Sandrine Hughes, Xavier Hanoulle, Benjamin Grenierboley, Florie DemiautteAbstract:Although APP metabolism is being intensively investigated, a large fraction of its modulators is yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimer's disease (AD), as a potential key modulator of axon guidance, a neuronal process that depends on the regulation of APP metabolism. We found that FERMT2 directly interacts with APP to modulate its metabolism, and that FERMT2 underexpression impacts axonal growth, synaptic connectivity, and long-term potentiation in an APP-dependent manner. Last, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3'UTR of FERMT2, induced a downregulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 underexpression in neurons and insight into how this may influence AD pathogenesis.
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alzheimer s genetic risk factor fermt2 kindlin 2 controls axonal growth and synaptic plasticity in an app dependent manner
bioRxiv, 2020Co-Authors: Fanny Eysert, Audrey Coulon, Emmanuelle Boscher, Anaїs-camille Vreulx, Amandine Flaig, Tiago Mendes, Sandrine Hughes, Xavier Hanoulle, Benjamin Grenierboley, Florie DemiautteAbstract:Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome-wide high-content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved. This approach highlighted the involvement of FERMT2 (or Kindlin-2), a genetic risk factor of Alzheimer′s disease (AD), as a potential key modulator of axon guidance; a neuronal process dependent on the APP metabolism regulation. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under-expression impacts axonal growth, synaptic connectivity and long-term potentiation in an APP-dependent manner. Lastly, the rs7143400-T allele, which is associated with an increased AD risk and localized within the 3′UTR of FERMT2, induced a down-regulation of FERMT2 expression through binding of miR-4504 among others. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls. Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under-expression in neurons and insight on how this may influence AD pathogenesis.