Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis

Abstract

Despite the critical role of endothelial Wnt/β-catenin signaling during central nervous system (CNS) vascularization, how endothelial cells sense and respond to specific Wnt ligands and what aspects of the multistep process of intra-cerebral blood vessel morphogenesis are controlled by these angiogenic signals remain poorly understood. We addressed these questions at single-cell resolution in zebrafish embryos. We identify the GPI-anchored MMP inhibitor Reck and the adhesion GPCR Gpr124 as integral components of a Wnt7a/Wnt7b-specific signaling complex required for brain angiogenesis and dorsal root ganglia neurogenesis. We further show that this atypical Wnt/β-catenin signaling pathway selectively controls endothelial tip cell function and hence, that mosaic restoration of single wild-type tip cells in Wnt/β-catenin-deficient perineural vessels is sufficient to initiate the formation of CNS vessels. Our results identify molecular determinants of ligand specificity of Wnt/β-catenin signaling and provide evidence for organ-specific control of vascular invasion through tight modulation of tip cell function.DOI: http://dx.doi.org/10.7554/eLife.06489.001

Defective adgra2 (gpr124) splicing and function in zebrafish ouchless mutants

“…The ouchless phenotypes are remarkably analogous to the DRG defects reported in adgra2 (previously known as gpr124) mutants (Vanhollebeke et al, 2015). Adgra2 is a newly discovered Wnt7-specific co-activator of Wnt/β-catenin signaling (Posokhova et al, 2015;Vanhollebeke et al, 2015;Zhou and Nathans, 2014).…”

“…Adgra2 is a newly discovered Wnt7-specific co-activator of Wnt/β-catenin signaling (Posokhova et al, 2015;Vanhollebeke et al, 2015;Zhou and Nathans, 2014). Along with Reck, it has been shown to control DRG formation by activating Wnt signaling in neural crest-derived sox10:mRFP + ganglion cells (Vanhollebeke et al, 2015). In addition, Adgra2 and Reck function as essential regulators of brain vascular development by promoting Wnt/ β-catenin signaling in cerebrovascular endothelial cells (ECs) (Posokhova et al, 2015;Ulrich et al, 2016;Vanhollebeke et al, 2015;Zhou and Nathans, 2014).…”

“…Adgra2 is a newly discovered Wnt7-specific co-activator of Wnt/β-catenin signaling (Posokhova et al, 2015;Vanhollebeke et al, 2015;Zhou and Nathans, 2014). Along with Reck, it has been shown to control DRG formation by activating Wnt signaling in neural crest-derived sox10:mRFP + ganglion cells (Vanhollebeke et al, 2015).…”

Cell behaviors and dynamics during angiogenesis

“…EC migration is triggered by a multitude of signaling pathways that can act in a particular manner on different blood vessels, and this selectivity is thought to be important for coordinating the simultaneous formation of separate blood vessels (Vanhollebeke et al, 2015;Wiley et al, 2011;Ulrich et al, 2016). In addition to activating signals, angiogenic sprouts encounter numerous guidance cues that ensure proper pathway finding (reviewed by Carmeliet and Tessier-Lavigne, 2005 invades all organs, it will be essential to dissect the relevant migratory cues in each case individually and identify attractive as well as repulsive cues in order to get a coherent and comprehensive picture of the mechanisms that regulate EC migration during angiogenesis (for examples, see Cha et al, 2012;Harrison et al, 2015;Tata et al, 2015;Thomas et al, 2013;Xu et al, 2014).…”

Cilostazol Promotes the Migration of Brain Microvascular Endothelial Cells

“…The migration process is regulated by multiple signaling pathways that can act in a different manner on different blood vessels, and this signaling selectivity is thought to contribute to the modulation of the simultaneous formation of separate blood vessels [31,33].…”