Cortical and retinal defects caused by dosage-dependent reductions in VEGF-A paracrine signaling.
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.
Haigh
Jody J
JJ
Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Canada.
Morelli
Paula I
PI
Gerhardt
Holger
H
Haigh
Katharina
K
Tsien
John
J
Damert
Annette
A
Miquerol
Lucile
L
Muhlner
Ulrich
U
Klein
Rudiger
R
Ferrara
Napoleone
N
Wagner
Erwin F
EF
Betsholtz
Christer
C
Nagy
Andras
A
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
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