Abstract
Development of the vertebrate eye requires signaling interactions between neural and non-neural tissues. Interactions between components of the vascular system and the developing neural retina have been difficult to decipher, however, due to the challenges of untangling these interactions from the roles of the vasculature in gas exchange. Here we use the embryonic zebrafish, which is not yet reliant upon hemoglobin-mediated oxygen transport, together with genetic strategies for (1) temporally-selective depletion of vascular endothelial cells, (2) elimination of blood flow through the circulation, and (3) elimination of cells of the erythroid lineage, including erythrocytes. The retinal phenotypes in these genetic systems were not identical, with endothelial cell-depleted retinas displaying laminar disorganization, cell death, reduced proliferation, and reduced cell differentiation. In contrast, the lack of blood flow resulted in a milder retinal phenotype showing reduced proliferation and reduced cell differentiation, indicating that an endothelial cell-derived factor(s) is/are required for laminar organization and cell survival. The lack of erythrocytes did not result in an obvious retinal phenotype, confirming that defects in retinal development that result from vascular manipulations are not due to poor gas exchange. These findings underscore the importance of the cardiovascular system supporting and controlling retinal development in ways other than supplying oxygen. In addition, these findings identify a key developmental window for these interactions and point to distinct functions for vascular endothelial cells vs. circulating factors.
Highlights
The vertebrate eye develops as an intricate collaboration among multiple tissue types (Bryan et al, 2020)
Vascular endothelial cells first appear adjacent to the zebrafish retina as the hyaloid vasculature begins to form around 18 hpf (Hartsock et al, 2014; Hashiura et al, 2017)
Vessels remained disrupted through 72 hpf, sporadic expression of mCherry was seen within the eye at this age (Figures 1C,D)
Summary
The vertebrate eye develops as an intricate collaboration among multiple tissue types (Bryan et al, 2020). In mouse, Wnt signals from extraocular mesenchyme are needed to pattern and maintain the posterior regions of the developing optic vesicle as retinal pigmented epithelium (RPE) rather than as neural retina (Bankhead et al, 2015) As another example, an unknown factor from the lens is required for maturation of the hyaloid vasculature in zebrafish (Hartsock et al, 2014). An alternative in vitro approach suggested that soluble factors from endothelial cells promote neural stem cell selfrenewal while inhibiting their differentiation (Shen et al, 2004) The understanding of these interactions in vivo is even less clear, due to the challenges in uncoupling developmental functions of the vasculature from its roles in gas exchange and nutrient delivery. An increased understanding of these functions would have applications for the many retinal disorders that involve abnormalities of the vasculature, including age-related macular degeneration (van Lookeren Campagne et al, 2014), retinopathy of prematurity (Hartnett, 2015), and diabetic retinopathy (Shin et al, 2014)
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