Radial glial neural progenitors regulate nascent brain vascular network stabilization via inhibition of Wnt signaling.
The cerebral cortex performs complex cognitive functions at the expense of tremendous energy consumption. Blood vessels in the brain are known to form stereotypic patterns that facilitate efficient oxygen and nutrient delivery. Yet little is known about how vessel development in the brain is normally regulated. Radial glial neural progenitors are well known for their central role in orchestrating brain neurogenesis. Here we show that, in the late embryonic cortex, radial glial neural progenitors also play a key role in brain angiogenesis, by interacting with nascent blood vessels and regulating vessel stabilization via modulation of canonical Wnt signaling. We find that ablation of radial glia results in vessel regression, concomitant with ectopic activation of Wnt signaling in endothelial cells. Direct activation of Wnt signaling also results in similar vessel regression, while attenuation of Wnt signaling substantially suppresses regression. Radial glial ablation and ectopic Wnt pathway activation leads to elevated endothelial expression of matrix metalloproteinases, while inhibition of metalloproteinase activity significantly suppresses vessel regression. These results thus reveal a previously unrecognized role of radial glial progenitors in stabilizing nascent brain vascular network and provide novel insights into the molecular cascades through which target neural tissues regulate vessel stabilization and patterning during development and throughout life.
Departments of Neuroscience and Neurology, University of Wisconsin-Madison, Madison, WI, USA.
Shang
S
Ma
Hyo Jun
HJ
Kwon
Heidi
H
Johng
Keling
K
Zang
Zhen
Z
Huang
D000818:Animals; D001921:Brain / Q000098:blood supply*; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply*; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis; D009457:Neuroglia / Q000378:metabolism; D051738:Origin Recognition Complex / Q000235:genetics*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011826:Radial Nerve / Q000196:embryology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
D005136:Eye Proteins; D018398:Homeodomain Proteins; C497229:Orc3 protein, mouse; D051738:Origin Recognition Complex; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D051153:Wnt Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9