title: Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling.
abstract: To determine the function of VEGF-A in nervous system development, we have utilized the Nestin promoter-driven Cre recombinase transgene, in conjunction with a conditional and hypomorphic VEGF-A allele, to lower VEGF-A activity in neural progenitor cells. Mice with intermediate levels of VEGF-A activity showed decreased blood vessel branching and density in the cortex and retina, resulting in a thinner retina and aberrant structural organization of the cortex. Severe reductions in VEGF-A led to decreases in vascularity and subsequent hypoxia, resulting in the specific degeneration of the cerebral cortex and neonatal lethality. Decreased neuronal proliferation and hypoxia was evident at E11.5, leading to increased neuronal apoptosis in the cortex by E15.5. In order to address whether the observed changes in the structural organization of the nervous system were due to a direct and autocrine role of VEGF-A on the neural population, we conditionally inactivated the main VEGF-A receptor, Flk1, specifically in neuronal lineages, by using the Nestin Cre transgene. The normality of these mice ruled out the possibility that VEGF-A/Flk1 signaling has a significant autocrine role in CNS development. VEGF-A dosage is therefore a critical parameter regulating the density of the vascular plexus in the developing CNS that is in turn a key determinant in the development and architectural organization of the nervous system.
authors.affiliation: Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Canada.
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
authors.forename: Paula I
authors.initials: PI
authors.lastname: Morelli
authors.forename: Holger
authors.initials: H
authors.lastname: Gerhardt
authors.forename: Katharina
authors.initials: K
authors.lastname: Haigh
authors.forename: John
authors.initials: J
authors.lastname: Tsien
authors.forename: Annette
authors.initials: A
authors.lastname: Damert
authors.forename: Lucile
authors.initials: L
authors.lastname: Miquerol
authors.forename: Ulrich
authors.initials: U
authors.lastname: Muhlner
authors.forename: Rudiger
authors.initials: R
authors.lastname: Klein
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000002:abnormalities*; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology; D009419:Nerve Tissue Proteins; D064231:Nestin; D019899:Paracrine Communication / Q000502:physiology*; D012160:Retina / Q000002:abnormalities*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D042461:Vascular Endothelial Growth Factor A; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases