We have recently published that light entrainment of the local circadian clock in the retina is dependent on Opsin 5 (OPN5) and that Opn5 is expressed in a subset of retinal ganglion cells (RGCs). In preliminary analysis we have also shown, (1) that mice mutated for Opn5 or in clock genes (Per2 and Bmal1) have vascular development defects in both the retina and hyaloid vessels, and (2) using ChIP-seq analysis, that the vascular modulators Flt1 and EphrinB2 are directly regulated by the clock transcription factor BMAL1. Based on these data, we propose a model to explain the mechanism by which OPN5 regulates vascular development. In this model we suggest that light stimulation of OPN5 in RGCs first entrains a circadian clock in the neurons of the inner retina. We suggest that in turn, the clock transcription factor BMAL1 directly regulates rhythmic expression of Flt1 and EphrinB2. Since these are crucial regulators of the VEGFA (vascular endothelial growth factor A) response, this provides a direct link to the regulation of retinal angiogenesis and hyaloid vessel regression. Our central hypothesis is that an OPN5-dependent, local retinal clock regulates expression of Flt1 and EphrinB2 and, in turn, light-dependent vascular development of the eye. To investigate this hypothesis, we propose three aims. We will determine when during development the OPN5-dependent retinal clock is first active (Aim 1), whether retinal clock function is required for normal vascular development (Aim 2) and whether Flt1, EphrinB2 and other vascular mediators are regulated by an OPN5-dependent retinal clock. The existence of an OPN5-dependent pathway that regulates vascular responses in the eye is an unusual finding that may have important implications for the human vascular retinopathies.

Public Health Relevance

In this project we will investigate how a circadian clock in the retina regulates the development of the vascular system in the eye. This work may teach us how daily lighting conditions influence some disease conditions including age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Greenwell, Thomas
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Cincinnati Children's Hospital Medical Center
United States
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Nayak, Gowri; Odaka, Yoshinobu; Prasad, Vikram et al. (2018) Developmental vascular regression is regulated by a Wnt/?-catenin, MYC and CDKN1A pathway that controls cell proliferation and cell death. Development 145:
Sawant, Onkar B; Horton, Amanda M; Zucaro, Olivia F et al. (2017) The Circadian Clock Gene Bmal1 Controls Thyroid Hormone-Mediated Spectral Identity and Cone Photoreceptor Function. Cell Rep 21:692-706
Charette, Jeremy R; Earp, Sarah E; Bell, Brent A et al. (2017) A mutagenesis-derivedLrp5mouse mutant with abnormal retinal vasculature and low bone mineral density. Mol Vis 23:140-148
Sakabe, Masahide; Fan, Jieqing; Odaka, Yoshinobu et al. (2017) YAP/TAZ-CDC42 signaling regulates vascular tip cell migration. Proc Natl Acad Sci U S A 114:10918-10923