Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis

Abstract

Despite the importance of CNS blood vessels, the molecular mechanisms that regulate CNS angiogenesis and blood−brain barrier (BBB) formation are largely unknown. Here we analyze the role of Wnt/β-catenin signaling in regulating the formation of CNS blood vessels. First, through the analysis of TOP-Gal Wnt reporter mice, we identify that canonical Wnt/β-catenin signaling is specifically activated in CNS, but not non-CNS, blood vessels during development. This activation correlates with the expression of different Wnt ligands by neural progenitor cells in distinct locations throughout the CNS, including Wnt7a and Wnt7b in ventral regions and Wnt1, Wnt3, Wnt3a, and Wnt4 in dorsal regions. Blockade of Wnt/β-catenin signaling in vivo specifically disrupts CNS, but not non-CNS, angiogenesis. These defects include reduction in vessel number, loss of capillary beds, and the formation of hemorrhagic vascular malformations that remain adherent to the meninges. Furthermore, we demonstrate that Wnt/β-catenin signaling regulates the expression of the BBB-specific glucose transporter glut-1. Taken together these experiments reveal an essential role for Wnt/β-catenin signaling in driving CNS-specific angiogenesis and provide molecular evidence that angiogenesis and BBB formation are in part linked.

The Blood–Brain Barrier

“…Comparative microarray analysis has identified that effectors of Wnt/b-catenin signaling, including Lef1, Apcdd1, and tnfrsf19, are enriched CNS ECs compared to ECs in peripheral organs (Daneman et al 2009(Daneman et al , 2010a. Transgenic reporter mice have confirmed that Wnt/ b-catenin signaling is activated in CNS ECs during embryonic angiogenesis (Liebner et al 2008;Stenman et al 2008;Daneman et al 2009).…”

“…Comparative microarray analysis has identified that effectors of Wnt/b-catenin signaling, including Lef1, Apcdd1, and tnfrsf19, are enriched CNS ECs compared to ECs in peripheral organs (Daneman et al 2009(Daneman et al , 2010a. Transgenic reporter mice have confirmed that Wnt/ b-catenin signaling is activated in CNS ECs during embryonic angiogenesis (Liebner et al 2008;Stenman et al 2008;Daneman et al 2009). Different Wnt ligands are secreted by neural stem cells and neural progenitors in spatially distinct regions, notably Wnt7a and Wnt7b in ventral regions and Wnt1, Wnt3, Wnt 3a, and Wnt4 in dorsal regions (Stenman et al 2008;Daneman et al 2009).…”

“…2) (Li et al 2001(Li et al , 2002Enerson and Drewes 2006;Cayrol et al 2008;Daneman et al 2009Daneman et al , 2010aOhtsuki et al 2014). Recently, the use of large-scale genomic and proteomic experimental approaches has provided greater detail and understanding of the molecular biology of the BBB.…”

“…In particular, Wnt/bcatenin signaling through Lef1, as well as Sonic hedgehog signaling through Gli have been shown to be important for regulating the formation and function of the BBB (Liebner et al 2008;Stenman et al 2008;Daneman et al 2009;Alvarez et al 2011a). In addition, vascular metabolism has been implicated in regulating barrier properties of CNS vasculature by metabolizing potential toxins or altering the properties of molecules (Fig.…”

“…Recent work in genetic mouse models has shown that there is a unique angiogenic program driving vessel formation in the CNS regulated by Wnt/b-catenin that also induces specific barrier properties in CNS ECs (Liebner et al 2008;Stenman et al 2008;Daneman et al 2009). Comparative microarray analysis has identified that effectors of Wnt/b-catenin signaling, including Lef1, Apcdd1, and tnfrsf19, are enriched CNS ECs compared to ECs in peripheral organs (Daneman et al 2009(Daneman et al , 2010a.…”