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A direct and melanopsin-dependent fetal light response regulates mouse eye development

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Abstract

Vascular patterning is critical for organ function. In the eye, there is simultaneous regression of embryonic hyaloid vasculature1 (important to clear the optical path) and formation of the retinal vasculature2 (important for the high metabolic demands of retinal neurons). These events occur postnatally in the mouse. Here we have identified a light-response pathway that regulates both processes. We show that when mice are mutated in the gene (Opn4) for the atypical opsin melanopsin3,4,5, or are dark-reared from late gestation, the hyaloid vessels are persistent at 8 days post-partum and the retinal vasculature overgrows. We provide evidence that these vascular anomalies are explained by a light-response pathway that suppresses retinal neuron number, limits hypoxia and, as a consequence, holds local expression of vascular endothelial growth factor (VEGFA) in check. We also show that the light response for this pathway occurs in late gestation at about embryonic day 16 and requires the photopigment in the fetus and not the mother. Measurements show that visceral cavity photon flux is probably sufficient to activate melanopsin-expressing retinal ganglion cells in the mouse fetus. These data thus show that light—the stimulus for function of the mature eye—is also critical in preparing the eye for vision by regulating retinal neuron number and initiating a series of events that ultimately pattern the ocular blood vessels.

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Figure 1: Hyaloid regression is regulated by light.
Figure 2: Hyaloid regression and retinal angiogenesis are regulated by melanopsin.
Figure 3: Light and melanopsin-dependent regulation of VEGFA expression and hypoxia in the retina.
Figure 4: Gestational light controls vascular development in the eye.

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Acknowledgements

We thank D. Bredl, P. Speeg and M. Sarangdhar for technical assistance, A. Delwig and N. Brown for advice. We acknowledge the assistance of the Research Flow Cytometry Core in the Division of Rheumatology at CCHMC, supported in part by NIH AR-47363. This work was supported by the NIH (R.A.L., D.R.C., J.M.K. and R.S.H.) with additional funding from the Abrahamson Pediatric Eye Institute of CCHMC, That Man May See at UCSF, Research to Prevent Blindness (D.R.C.) and March of Dimes (D.R.C.).

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R.A.L. and D.R.C. provided project leadership. R.A.L., D.R.C. and S.R. wrote the manuscript. R.A.L., D.R.C. and R.S.H. supervised experimental work. N.F. developed critical reagents and M.B.Y. provided important clinical insights. S.R., C.C., J.F., J.M.K. and D.R.C. performed experimentation and analysis.

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Correspondence to David R. Copenhagen or Richard A. Lang.

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Competing interests

N.F. is an employee of Genentech Corporation.

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Rao, S., Chun, C., Fan, J. et al. A direct and melanopsin-dependent fetal light response regulates mouse eye development. Nature 494, 243–246 (2013). https://doi.org/10.1038/nature11823

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