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

BMC Genomics

Research Article

Hazel Holden¹  Paul Kasher¹  Alice Brockington¹  Pamela J Shaw¹  Paul R Heath¹  Michael Sendtner²  Florian LP Bender²  Peter Carmeliet³  Filip Claes³  Diether Lambrechts³ 

[1] Academic Neurology Unit, University of Sheffield, E Floor, Medical School, Beech Hill Road, S10 2RX, Sheffield, UK;Institute for Clinical Neurobiology, University of Würzburg, D-97080, Würzburg, Germany;Vesalius Research Centre, VIB - KULeuven, Leuven, Belgium;

关键词: Vascular Endothelial Growth Factor;    Gene Ontology;    Amyotrophic Lateral Sclerosis;    Vascular Endothelial Growth Factor Expression;    Nervous System Development;   

DOI  :  10.1186/1471-2164-11-203

 received in 2009-11-16, accepted in 2010-03-26,  发布年份 2010

来源: Springer

【 摘 要 】

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

【 授权许可】

Unknown   
© Brockington et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. 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.