Reduced mTORC1‐signaling in retinal ganglion cells leads to vascular retinopathy

Abstract

Background: The coordinated wiring of neurons, glia and endothelial cells into neurovascular units is critical for central nervous system development. This is best exemplified in the mammalian retina where interneurons, astrocytes and retinal ganglion cells sculpt their vascular environment to meet the metabolic demands of visual function. Identifying the molecular networks that underlie neurovascular unit formation is an important step towards a deeper understanding of nervous system development and function. Results: Here, we report that cell-to-cell mTORC1-signaling is essential for neurovascular unit formation during mouse retinal development. Using a conditional knockout approach we demonstrate that reduced mTORC1 activity in asymmetrically positioned retinal ganglion cells induces a delay in postnatal vascular network formation in addition to the production of rudimentary and tortuous vessel networks in adult animals. The severity of this vascular phenotype is directly correlated to the degree of mTORC1 down regulation within the neighboring retinal ganglion cell population.Conclusions: This study establishes a cell nonautonomous role for mTORC1-signaling during retinal development. These findings contribute to our current understanding of neurovascular unit formation and demonstrate how ganglion cells actively sculpt their local environment to ensure that the retina is perfused with an appropriate supply of oxygen and nutrients.

ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

“…Three right retinas from three animals (n = 3) were used for wholemount staining. Wholemounts were treated with 1% Triton X-100 in 0.1 M PBS (40 min) before NDS (1 h), and antibody against isolectin B4-Alexa 488 (IB4, molecular probe, 1:200) 73 was diluted in 0.5% Triton X-100 in 0. for entire wholemount images). For retinal vasculature assessment in Atf6 −/− mice, confocal micrographs of the wholemounts (n = 3, animals per group) were taken at the nerve fiber layer (superficial layer), at the IPL (intermediate layer), and at the OPL (deep layer) of the dorsal regions (1 mm away from optic disc) of the retina.…”