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. Author manuscript; available in PMC: 2019 Oct 1.
Published in final edited form as: Nat Cell Biol. 2019 Apr 1;21(4):420–429. doi: 10.1038/s41556-019-0301-x

Figure 5. OPN5 RGCs use Vgat in a hyaloid regression pathway: A model for OPN4-VEGFA and OPN5-dopamine pathway integration.

Figure 5.

a, Quantification of hyaloid vessels in P8 Opn5+/+; Vglut2+/+ (light grey), Opn5+/cre; Vglut2+/+ (dark grey), Opn5+/cre; Vglut2fl/+ (light blue), Opn5+/cre; Vglut2fl/fl (dark blue) mice. b-e, Hyaloids from P8 Opn5+/+; Vgat+/+ (b), Opn5+/cre; Vgat+/+ (c), Opn5+/cre; Vgatfl/+ (d), Opn5+/cre; Vgatfl/fl (e) mice. f, Quantification of hyaloid vessels in P8 mice with genotypes listed in b-e. g-h, Retinal cryosections imaged for phospho-T53-DAT (red) and Ai6 cre (green) from P8 Ai6; Opn5cre; Vgat+/+ (g,h) or Ai6; Opn5cre; Vgatfl/fl (i, j) mice. Additional examples of (g-j) available on Figshare. Sample size (n) for a,f is shown at the base of each bar and represents mice. p values by one-way ANOVA. Error bars are SEM. Images in b-e represent at least six, and in g-j at least three, separate experiments. Scale bars 200 μm (b-e) 20 μm (g-j). k, l, Schematic describing integration of the OPN4-VEGFA and OPN5-dopamine hyaloid regression pathways. The schematic identifies two phases of development, E16-E18 (k), and P3-P8 (l), when OPN4 and OPN5 are each required. In late gestation, blue light stimulation of OPN4 RGCs suppresses retinal cellularity. In dark-reared or in Opn4 null mice, elevated cellularity increases oxygen demand ([O2]) and, via the hypoxia response pathway, increases VEGFA expression in amacrine cells and RGCs. Elevated VEGFA causes promiscuous retinal angiogenesis and suppresses hyaloid vessel regression. According to the present analysis, violet light stimulation of OPN5 RGCs postnatally suppresses dopamine in the vitreous by upregulating T53 phosphorylation of the dopamine transporter (P-DAT/SLC6A3) in neurons in the inner plexiform layer. Normally, OPN5-dependent phosphorylation of DAT results in elevated dopamine uptake and a reduced flux of dopamine from dopaminergic amacrine cells to the vitreous. In the absence of OPN5, or the violet light that stimulates OPN5, vitreous dopamine is precociously elevated. This results in premature activation of dopamine receptor DRD2 in hyaloid VECs, suppression of VEGFR2 survival signalling and precocious regression. These data indicate that both 480 nm blue light via OPN4, and 380 nm violet light via OPN5, function as developmental timing cues.