Toma, Kenichi, Zhao, Mengya, Zhang, Shaobo, Wang, Fei, Graham, Hannah K., Zou, Jun, Modgil, Shweta, Shang, Wenhao H., Tsai, Nicole Y., Cai, Zhishun, Liu, Liping, Hong, Guiying, Kriegstein, Arnold R., Hu, Yang, Körbelin, Jakob, Zhang, Ruobing, Liao, Yaping Joyce, Kim, Tyson N., Ye, Xin, and Duan, Xin
The vasculature of the central nervous system is a 3D lattice composed of laminar vascular beds interconnected by penetrating vessels. The mechanisms controlling 3D lattice network formation remain largely unknown. Combining viral labeling, genetic marking, and single-cell profiling in the mouse retina, we discovered a perivascular neuronal subset, annotated as Fam19a4/Nts-positive retinal ganglion cells (Fam19a4/Nts-RGCs), directly contacting the vasculature with perisomatic endfeet. Developmental ablation of Fam19a4/Nts-RGCs led to disoriented growth of penetrating vessels near the ganglion cell layer (GCL), leading to a disorganized 3D vascular lattice. We identified enriched PIEZO2 expression in Fam19a4/Nts-RGCs. Piezo2 loss from all retinal neurons or Fam19a4/Nts-RGCs abolished the direct neurovascular contacts and phenocopied the Fam19a4/Nts-RGC ablation deficits. The defective vascular structure led to reduced capillary perfusion and sensitized the retina to ischemic insults. Furthermore, we uncovered a Piezo2-dependent perivascular granule cell subset for cerebellar vascular patterning, indicating neuronal Piezo2-dependent 3D vascular patterning in the brain. [Display omitted] • Fam19a4/Nts-RGCs directly contact blood vessels with perisomatic endfeet • Ablation of Fam19a4/Nts-RGCs disrupts the perpendicular penetrating vessel growth • Fam19a4/Nts-RGCs utilize neuronal Piezo2 to guide 3D vascular lattice organization • Disorganized 3D vascular lattice impairs capillary perfusion and visual function Perivascular neurons guide the spatial orientation of penetrating vessels via Piezo2 to pattern the 3D vascular lattice in the developing mouse retina. This neuron-guided vascular patterning is critical for capillary perfusion of the retina and protection from ischemic challenge, progressive retinal neuron loss, and visual impairment. [ABSTRACT FROM AUTHOR]