RESUMO
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.
Assuntos
Encéfalo/irrigação sanguínea , Córtex Cerebral/irrigação sanguínea , Células-Tronco Neurais/metabolismo , Complexo de Reconhecimento de Origem/genética , Nervo Radial/embriologia , Animais , Pontos de Checagem do Ciclo Celular , Células Cultivadas , Proteínas do Olho/genética , Feminino , Proteínas de Homeodomínio/genética , Masculino , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Transgênicos , Neovascularização Fisiológica , Neurogênese , Neuroglia/metabolismo , Fator de Transcrição PAX6 , Fatores de Transcrição Box Pareados/genética , RNA Mensageiro/biossíntese , Nervo Radial/metabolismo , Proteínas Repressoras/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Via de Sinalização WntRESUMO
Neurotensin receptor type 1 (NTS1) is known to mediate a variety of biological functions of neurotensin (NT) in the central nervous system. In this study, we found that NTS1 null mice displayed decreased sensitivity to the ataxic effect of ethanol on the rotarod and increased ethanol consumption when given a free choice between ethanol and tap water containing bottles. Interestingly, the administration of NT69L, a brain-permeable NT analog, increased ethanol sensitivity in wild-type littermates but had no such effect in NTS1 null mice, suggesting that NTS1 contributes to NT-mediated ethanol intoxication. Furthermore, the daily treatment of NT69L, for 4 consecutive days, significantly reduced alcohol preference and consumption in wild-type littermates but had no such effects in NTS1 null mice in a two-bottle drinking experiment. Our study provides evidence for possible pharmacological roles of NT69L in which it increases sensitivity to the ataxic effect, and decreases voluntary consumption, of ethanol. Our study also demonstrates NTS1-mediated behavioral effects of NT69L. Therefore, our findings will be useful for understanding some aspects of alcoholism as well as to develop novel pharmacological therapeutic options for humans.