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PMID: 20346106 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Downregulation of genes with a function in axon outgrowth and synapse formation in motor neurones of the VEGFdelta/delta mouse model of amyotrophic lateral sclerosis.

BMC genomics ·Vol. 11 ·2010-03-26 ·Pages 203

Brockington A, Heath PR, Holden H, Kasher P, Bender FL, Claes F, Lambrechts D, Sendtner M, Carmeliet P, Shaw PJ

Abstract

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 VEGFdelta/delta mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease. 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 VEGFdelta/delta 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. VEGFdelta/delta 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 VEGFdelta/delta 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 VEGFdelta/delta mice, axon outgrowth is significantly reduced compared to wild-type littermates. 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.

MeSH Terms
Amyotrophic Lateral Sclerosis/metabolism Animals Axons/metabolism Cholesterol/metabolism Down-Regulation Female Mice Mice, Transgenic Mitochondria/metabolism Motor Neurons/metabolism RNA Processing, Post-Transcriptional Synapses Vascular Endothelial Growth Factor A
Chemicals
Vascular Endothelial Growth Factor A Cholesterol
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Brockington Alice
Academic Neurology Unit, University of Sheffield, E Floor, Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
Heath Paul R
Holden Hazel
Kasher Paul
Bender Florian L P
Claes Filip
Lambrechts Diether
Sendtner Michael
Carmeliet Peter
Shaw Pamela J
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Article Info
Journal
BMC genomics
Abbr.
BMC Genomics
ISSN
1471-2164
DOI
10.1186/1471-2164-11-203
Published
2010-03-26
Epub
2010-00-26
Pages
203
Language
English
Region
England
NLM ID
100965258
PMCID
PMC2861063
Subset
IM
Grants
Wellcome Trust · United Kingdom
External Links
PubMed source DOI: 10.1186/1471-2164-11-203 PMC Full Text View journal details
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