Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome
The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the...
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Format: | Article |
Language: | English |
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Elsevier
2017-04-01
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Series: | Neurobiology of Disease |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116302959 |
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doaj-5e38574c4d1c4b5c82d021b2a96eb852 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alix Trouillet Henri Lorach Elisabeth Dubus Brahim El Mathari Ivana Ivkovic Julie Dégardin Manuel Simonutti Michel Paques Xavier Guillonneau Florian Sennlaub José-Alain Sahel Pierre Ronco Emmanuelle Plaisier Serge Picaud |
spellingShingle |
Alix Trouillet Henri Lorach Elisabeth Dubus Brahim El Mathari Ivana Ivkovic Julie Dégardin Manuel Simonutti Michel Paques Xavier Guillonneau Florian Sennlaub José-Alain Sahel Pierre Ronco Emmanuelle Plaisier Serge Picaud Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome Neurobiology of Disease Collagen Retinal damage Mouse model Vascular permeability |
author_facet |
Alix Trouillet Henri Lorach Elisabeth Dubus Brahim El Mathari Ivana Ivkovic Julie Dégardin Manuel Simonutti Michel Paques Xavier Guillonneau Florian Sennlaub José-Alain Sahel Pierre Ronco Emmanuelle Plaisier Serge Picaud |
author_sort |
Alix Trouillet |
title |
Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome |
title_short |
Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome |
title_full |
Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome |
title_fullStr |
Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome |
title_full_unstemmed |
Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndrome |
title_sort |
col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of hanac syndrome |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2017-04-01 |
description |
The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling. Summary statement: This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition. |
topic |
Collagen Retinal damage Mouse model Vascular permeability |
url |
http://www.sciencedirect.com/science/article/pii/S0969996116302959 |
work_keys_str_mv |
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doaj-5e38574c4d1c4b5c82d021b2a96eb8522021-03-22T12:45:03ZengElsevierNeurobiology of Disease1095-953X2017-04-011005261Col4a1 mutation generates vascular abnormalities correlated with neuronal damage in a mouse model of HANAC syndromeAlix Trouillet0Henri Lorach1Elisabeth Dubus2Brahim El Mathari3Ivana Ivkovic4Julie Dégardin5Manuel Simonutti6Michel Paques7Xavier Guillonneau8Florian Sennlaub9José-Alain Sahel10Pierre Ronco11Emmanuelle Plaisier12Serge Picaud13INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceFovea Sanofi, Paris, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France; CHNO des Quinze-Vingts, Paris, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, FranceINSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France; CHNO des Quinze-Vingts, Paris, France; Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; Academie des Sciences, Paris, FranceAP HP, Department of Nephrology, Tenon Hospital, Paris, France; INSERM, U1155, Paris F-75020, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS_1155, Paris F-75020, FranceAP HP, Department of Nephrology, Tenon Hospital, Paris, France; INSERM, U1155, Paris F-75020, France; Sorbonne Universités, UPMC Univ Paris 06, UMRS_1155, Paris F-75020, France; Correspondence to: E. Plaisier, Department of Nephrology, Bâtiment Recherche, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France.INSERM, U968, Institut de la Vision, Paris F-75012, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S968, Institut de la Vision, Paris, F-75012, France; CNRS UMR7210, Institut de la Vision, Paris 75012, France; Correspondence to: S. Picaud, Institut de la Vision, 17 rue Moreau, 75012 Paris, France.The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling. Summary statement: This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition.http://www.sciencedirect.com/science/article/pii/S0969996116302959CollagenRetinal damageMouse modelVascular permeability |