Abstract
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. 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. 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.
Highlights
The coordinated development of neurovascular units is critical for the function of the central nervous system (CNS).[1]
Differentiation program to produce six neuronal and one glial cell-type that become positioned within three stratified layers: (1) rod and cone photoreceptors reside in the outer nuclear layer, (2) interneurons and Müller glia are localized within the inner nuclear layer while (3) retinal ganglion cells (RGCs) and displaced amacrine cells are situated in the ganglion cell layer (GCL).[2,3]
This study describes a cell nonautonomous role for mammalian target of rapamycin complex 1 (mTORC1) signaling during retinal neurovascular development
Summary
The coordinated development of neurovascular units is critical for the function of the central nervous system (CNS).[1]. Growing evidence derived from mouse models demonstrates that retinal neurons are directly involved in sculpting their vascular environment.[8,9,10] For example, a reduction in RGC number and activity leads to the irregular development of the neighboring superficial plexus.[11,12,13,14,15] In a similar manner, genetic ablation of either horizontal or amacrine cells reveals that these neurons are required for deep and intermediate plexus formation while spontaneous activity of these interneurons is required to maintain the function of the adjacent intraretinal vascular network.[7,16,17] long-term neurovascular uncoupling affects retinal homeostasis and drives the progressive development of vascular pathologies.[18,19,20,21] This is best exemplified by diseases such as diabetic retinopathy and retinopathy of prematurity which are amongst the leading causes of visual impairment and blindness.[22,23] The generation of novel mouse models that identify the signaling complexes involved in the establishment and maintenance of neurovascular units are crucial to broaden our understanding of retinal development and disease.[24]. Our findings contribute to the current understanding of neuronal and endothelial cell cross-talk and demonstrate how retinal neurons signal through mTORC1 to sculpt the neighboring vascular environment
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Schedule a callMore From: Developmental dynamics : an official publication of the American Association of Anatomists
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