title: Vascular endothelial growth factor (VEGF) isoform regulation of early forebrain development.
abstract: This work was designed to determine the role of the vascular endothelial growth factor A (VEGF) isoforms during early neuroepithelial development in the mammalian central nervous system (CNS), specifically in the forebrain. An emerging model of interdependence between neural and vascular systems includes VEGF, with its dual roles as a potent angiogenesis factor and neural regulator. Although a number of studies have implicated VEGF in CNS development, little is known about the role that the different VEGF isoforms play in early neurogenesis. We used a mouse model of disrupted VEGF isoform expression that eliminates the predominant brain isoform, VEGF164, and expresses only the diffusible form, VEGF120. We tested the hypothesis that VEGF164 plays a key role in controlling neural precursor populations in developing cortex. We used microarray analysis to compare gene expression differences between wild type and VEGF120 mice at E9.5, the primitive stem cell stage of the neuroepithelium. We quantified changes in PHH3-positive nuclei, neural stem cell markers (Pax6 and nestin) and the Tbr2-positive intermediate progenitors at E11.5 when the neural precursor population is expanding rapidly. Absence of VEGF164 (and VEGF188) leads to reduced proliferation without an apparent effect on the number of Tbr2-positive cells. There is a corresponding reduction in the number of mitotic spindles that are oriented parallel to the ventricular surface relative to those with a vertical or oblique angle. These results support a role for the VEGF isoforms in supporting the neural precursor population of the early neuroepithelium.
authors.affiliation: University of North Dakota, Department of Biology, Grand Forks, ND 58202, USA. diane.darland@email.und.edu
authors.forename: Diane C
authors.initials: DC
authors.lastname: Darland
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Cain
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Berosik
authors.forename: Magali
authors.initials: M
authors.lastname: Saint-Geniez
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Odens
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Schaubhut
authors.forename: Sarah
authors.initials: S
authors.lastname: Frisch
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.forename: Tristan
authors.initials: T
authors.lastname: Darland
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
mesh_terms: D000818:Animals; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000502:physiology*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016548:Prosencephalon / Q000196:embryology*; D020033:Protein Isoforms / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000502:physiology*
chemical_list: D017931:DNA Primers; D005136:Eye Proteins; D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D020033:Protein Isoforms; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse