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Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis
BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that stimulates vasculogenesis. It has also been shown to act as a neurotrophic factor in vitro and in vivo. Deletion of the hypoxia response element of the promoter region of the gene encoding VEGF in mice causes a...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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BioMed Central
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861063/ https://www.ncbi.nlm.nih.gov/pubmed/20346106 http://dx.doi.org/10.1186/1471-2164-11-203 |
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author | Brockington, Alice Heath, Paul R Holden, Hazel Kasher, Paul Bender, Florian LP Claes, Filip Lambrechts, Diether Sendtner, Michael Carmeliet, Peter Shaw, Pamela J |
author_facet | Brockington, Alice Heath, Paul R Holden, Hazel Kasher, Paul Bender, Florian LP Claes, Filip Lambrechts, Diether Sendtner, Michael Carmeliet, Peter Shaw, Pamela J |
author_sort | Brockington, Alice |
collection | PubMed |
description | BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that stimulates vasculogenesis. It has also been shown to act as a neurotrophic factor in vitro and in vivo. Deletion of the hypoxia response element of the promoter region of the gene encoding VEGF in mice causes a reduction in neural VEGF expression, and results in adult-onset motor neurone degeneration that resembles amyotrophic lateral sclerosis (ALS). Investigating the molecular pathways to neurodegeneration in the VEGF(δ/δ )mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease. RESULTS: Microarray analysis was used to determine the transcriptional profile of laser captured spinal motor neurones of transgenic and wild-type littermates at 3 time points of disease. 324 genes were significantly differentially expressed in motor neurones of presymptomatic VEGF(δ/δ )mice, 382 at disease onset, and 689 at late stage disease. Massive transcriptional downregulation occurred with disease progression, associated with downregulation of genes involved in RNA processing at late stage disease. VEGF(δ/δ )mice showed reduction in expression, from symptom onset, of the cholesterol synthesis pathway, and genes involved in nervous system development, including axonogenesis, synapse formation, growth factor signalling pathways, cell adhesion and microtubule-based processes. These changes may reflect a reduced capacity of VEGF(δ/δ )mice for maintenance and remodelling of neuronal processes in the face of demands of neural plasticity. The findings are supported by the demonstration that in primary motor neurone cultures from VEGF(δ/δ )mice, axon outgrowth is significantly reduced compared to wild-type littermates. CONCLUSIONS: Downregulation of these genes involved in axon outgrowth and synapse formation in adult mice suggests a hitherto unrecognized role of VEGF in the maintenance of neuronal circuitry. Dysregulation of VEGF may lead to neurodegeneration through synaptic regression and dying-back axonopathy. |
format | Text |
id | pubmed-2861063 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-28610632010-04-29 Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis Brockington, Alice Heath, Paul R Holden, Hazel Kasher, Paul Bender, Florian LP Claes, Filip Lambrechts, Diether Sendtner, Michael Carmeliet, Peter Shaw, Pamela J BMC Genomics Research Article BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that stimulates vasculogenesis. It has also been shown to act as a neurotrophic factor in vitro and in vivo. Deletion of the hypoxia response element of the promoter region of the gene encoding VEGF in mice causes a reduction in neural VEGF expression, and results in adult-onset motor neurone degeneration that resembles amyotrophic lateral sclerosis (ALS). Investigating the molecular pathways to neurodegeneration in the VEGF(δ/δ )mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease. RESULTS: Microarray analysis was used to determine the transcriptional profile of laser captured spinal motor neurones of transgenic and wild-type littermates at 3 time points of disease. 324 genes were significantly differentially expressed in motor neurones of presymptomatic VEGF(δ/δ )mice, 382 at disease onset, and 689 at late stage disease. Massive transcriptional downregulation occurred with disease progression, associated with downregulation of genes involved in RNA processing at late stage disease. VEGF(δ/δ )mice showed reduction in expression, from symptom onset, of the cholesterol synthesis pathway, and genes involved in nervous system development, including axonogenesis, synapse formation, growth factor signalling pathways, cell adhesion and microtubule-based processes. These changes may reflect a reduced capacity of VEGF(δ/δ )mice for maintenance and remodelling of neuronal processes in the face of demands of neural plasticity. The findings are supported by the demonstration that in primary motor neurone cultures from VEGF(δ/δ )mice, axon outgrowth is significantly reduced compared to wild-type littermates. CONCLUSIONS: Downregulation of these genes involved in axon outgrowth and synapse formation in adult mice suggests a hitherto unrecognized role of VEGF in the maintenance of neuronal circuitry. Dysregulation of VEGF may lead to neurodegeneration through synaptic regression and dying-back axonopathy. BioMed Central 2010-03-26 /pmc/articles/PMC2861063/ /pubmed/20346106 http://dx.doi.org/10.1186/1471-2164-11-203 Text en Copyright ©2010 Brockington et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Brockington, Alice Heath, Paul R Holden, Hazel Kasher, Paul Bender, Florian LP Claes, Filip Lambrechts, Diether Sendtner, Michael Carmeliet, Peter Shaw, Pamela J Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis |
title | Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis |
title_full | Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis |
title_fullStr | Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis |
title_full_unstemmed | Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis |
title_short | Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGF(δ/δ )mouse model of amyotrophic lateral sclerosis |
title_sort | downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the vegf(δ/δ )mouse model of amyotrophic lateral sclerosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861063/ https://www.ncbi.nlm.nih.gov/pubmed/20346106 http://dx.doi.org/10.1186/1471-2164-11-203 |
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