TY - JOUR T1 - Neuropilin 1 sequestration by neuropathogenic mutant glycyl-tRNA synthetase is permissive to vascular development and homeostasis JF - bioRxiv DO - 10.1101/081513 SP - 081513 AU - James N. Sleigh AU - Adriana Gómez-Martín AU - Giampietro Schiavo Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/10/17/081513.abstract N2 - It remains a mystery how dominantly inherited mutations in the housekeeping gene GARS, which encodes glycyl-tRNA synthetase (GlyRS), mediate selective peripheral nerve toxicity resulting in the currently incurable Charcot-Marie-Tooth disease type 2D (CMT2D). A recent study identified the transmembrane receptor protein neuropilin 1 (Nrp1) as a substrate for aberrant extracellular binding of mutant GlyRS. Formation of the Nrp1/mutant GlyRS complex antagonises the interaction of Nrp1 with one of its main natural ligands, vascular endothelial growth factor-A (VEGF-A), contributing to neurodegeneration. Reduced binding of Nrp1 to VEGF-A is known to disrupt blood vessel development and growth. We therefore analysed capillary architecture at early and later symptomatic time points in CMT2D mouse muscles, retina, and sciatic nerve, as well as in embryonic hindbrain. Assessing capillary diameter, density, and branching, we observed no differences between wild-type and mutant animals from embryonic development to three months, spanning the duration over which numerous sensory and neuromuscular phenotypes manifest. This work indicates that mutant GlyRS-mediated disruption of Nrp1/VEGF-A signalling is permissive to capillary maturation and maintenance in CMT2D mice.Summary Statement Although the multi-functional neuropilin 1/VEGF-A signalling pathway is impaired by dominant pathogenic GlyRS variants, the vascular system remains unperturbed in Gars mutant mice.α-BTXα-bungarotoxinCMTD2Charcot-Marie-Tooth disease type 2DDSHBDevelopmental Studies Hybridoma BankGARSGlyRS geneGlyRSglycyl-tRNA synthetaseIB4isolectin B4Mbpmyelin basic proteinNrp1neuropilin 1PBSphosphate buffered salinePecam1platelet endothelial cell adhesion molecule 1PFAparaformaldehydeSEMA3Asemaphorin 3ASV2synaptic vesicle 2tRNAtransfer RNATVAtransversus abdominisVEGF-Avascular endothelial growth factor AVEGFR2vascular endothelial growth factor receptor 22H3neurofilament ER -