title: Shifts in the vascular endothelial growth factor isoforms result in transcriptome changes correlated with early neural stem cell proliferation and differentiation in mouse forebrain.
abstract: Regulation of neural stem cell (NSC) fate decisions is critical during the transition from a multicellular mammalian forebrain neuroepithelium to the multilayered neocortex. Forebrain development requires coordinated vascular investment alongside NSC differentiation. Vascular endothelial growth factor A (Vegf) has proven to be a pleiotrophic gene whose multiple protein isoforms regulate a broad range of effects in neurovascular systems. To test the hypothesis that the Vegf isoforms (120, 164, and 188) are required for normal forebrain development, we analyzed the forebrain transcriptome of mice expressing specific Vegf isoforms, Vegf120, VegfF188, or a combination of Vegf120/188. Transcriptome analysis identified differentially expressed genes in embryonic day (E) 9.5 forebrain, a time point preceding dramatic neuroepithelial expansion and vascular investment in the telencephalon. Meta-analysis identified gene pathways linked to chromosome-level modifications, cell fate regulation, and neurogenesis that were altered in Vegf isoform mice. Based on these gene network shifts, we predicted that NSC populations would be affected in later stages of forebrain development. In the E11.5 telencephalon, we quantified mitotic cells [Phospho-Histone H3 (pHH3)-positive] and intermediate progenitor cells (Tbr2/Eomes-positive), observing quantitative and qualitative shifts in these populations. We observed qualitative shifts in cortical layering at P0, particularly with Ctip2-positive cells in layer V. The results identify a suite of genes and functional gene networks that can be used to further dissect the role of Vegf in regulating NSC differentiation and downstream consequences for NSC fate decisions.
authors.affiliation: Department of Biology, University of North Dakota, Grand Forks, North Dakota.
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Cain
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Berosik
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Snyder
authors.forename: Natalie F
authors.initials: NF
authors.lastname: Crawford
authors.forename: Shirin I
authors.initials: SI
authors.lastname: Nour
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Schaubhut
authors.forename: Diane C
authors.initials: DC
authors.lastname: Darland
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002490:Central Nervous System / Q000098:blood supply; D003001:Cloning, Molecular; D004797:Enzyme-Linked Immunosorbent Assay; D004848:Epithelium / Q000502:physiology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005838:Genotype; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D008938:Mitosis / Q000235:genetics; D058953:Neural Stem Cells / Q000502:physiology*; D011247:Pregnancy; D016548:Prosencephalon / Q000166:cytology / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A
keywords: Pax6; Tbr2; VEGF; forebrain; neural development; neurogenesis