Abstract: Myopia prevalence is dramatically increasing in recent years and in cases in which the refractive error is greater than ?6.00 D this disease can lead to severe visual impairment as well as even blindness. Changes in visual input affect the balance between ocular growth and refractive power development. If a mismatch occurs during eye development, the severity of this error affects the degree of myopia. In different animal models of this disease, we found that spatial visual stimuli are essential for maintaining a stable refractive status and normal vision. This is evident because the effects of changes in temporal visual stimuli (e.g., flickering light) on this process depend on whether spatial information is present or absent in the visual environment. Furthermore, the frequency, wavelength and intensity of light are involved in controlling refraction development. However, the molecular mechanisms underlying light-induced refraction changes are still unclear. There is definitive evidence that dopamine (DA) is one of the regulators of this process. This retinal neurotransmitter released by dopaminergic amacrine cells appears to play an important role in vision-guided eye growth because its synthesis and release are positively associated with the light intensity and spatial stimuli impinging on the retina. We found that bright light enhances retinal DA synthesis, and attenuates form deprivation myopia (FDM) development via activation of the dopamine receptor 1 (D1R). A nonselective DA receptor agonist apomorphine (APO) inhibited FDM in dopamine receptor 2 (D2R) knockout mice. These individual similar effects of DA and APO in wildtype and D2R knockout mice suggest that D1R activation has a protective effect against myopia development. On the other hand, D2R activation instead appears to promote myopia development because either genetic D2R ablation or pharmacological inactivation of D2R also attenuates myopia development. Based on these results, we hypothesize that the visual environment regulates the retinal DA levels, which in turn affects the relative balance between D1R and D2R activation. When D1R is relatively hyperactivated, the ocular refractive status shifts towards hyperopia. In contrast, such an effect on D2Rpromotes the refractive status to shift in the opposite direction towards myopia.

Abstract: Dopamine is known as a key molecule in retinal signaling pathways regulating visually guided eye growth, as evidenced by reduced retinal dopamine levels in various species when experimental myopia is generated. However, in C57BL/6 mice our recent work demonstrated that neither retinal dopamine levels, retinal tyrosine hydroxylase (rate-limiting enzyme in dopamine synthesis) levels, nor dopaminergic amacrine cell density/morphology, were altered during the development of form-deprivation myopia (FDM). These results suggest that retinal dopamine is unlikely associated with FDM development in this mouse strain. The role of dopamine in refractive development was further explored in this mouse strain when retinal dopamine levels were reduced by intravitreal injections of 6-OHDA, a neurotoxin that specifically destroys dopaminergic neurons. The dose was so chosen that retinal dopamine levels were reduced, but no significant changes in electroretinographic responses were detected. 6-OHDA induced significant myopic shifts in refraction in a dose-dependent manner, suggesting the involvement of dopamine in normal refractive development. Biometric measurements of ocular dimensions revealed that 6-OHDA resulted in a shorter axial length and a steeper cornea, while form-deprivation led to a longer axial length without changing the corneal radius of curvature. These results strongly suggest that in addition to the dopamine-independent mechanism, a dopamine-dependent mechanism works for refractive development. We have obtained evidence, suggesting that the dopamine-independent mechanism might be related to intrinsically photosensitive retinal ganglion cells (ipRGCs). Firstly, selective ablation of ipRGCs with an immunotoxin resulted in myopic shifts in refraction. Secondly, form-deprivation induced less myopic shifts in animals with ipRGC ablation.

Abstract: Axon regeneration capacity declines in mature retinal ganglion cells (RGCs). While a number of transcription factors and signaling molecules have been implicated to the loss of regenerative potential of RGC axon, their upstream regulators are unclear. We investigated the association between developmental decline of RGC regenerative potential and age-related changes in microRNA (miRNA) expression and showed that loss of axon regenerative potential can be partially restored by upregulating miR-19a in RGCs in vitro and in vivo. Regulating miRNA expression represents a new potential therapeutic approach to resuscitate age-related loss of axon growth ability.

Abstract: Corneal injuries and infections are the leading cause of blindness worldwide. Thus, understanding the mechanisms that control healing of the damaged cornea is critical for the development of new therapies to promptly restore vision. Innate lymphoid cells (ILCs) are a recently identified heterogeneous cell population that has been reported to orchestrate immunity and promote tissue repair in the lungs and skin after injury. However, whether ILCs can modulate the repair process in the cornea remains poorly understood. We identified a population of cornea-resident group 2 ILCs (ILC2s) in mice that express CD127, T1/ST2, CD90, and cKit. This cell population was relatively rare in corneas at a steady state but increased after corneal epithelial abrasion. Moreover, ILC2s were maintained and expanded locally at a steady state and after wounding. Depletion of this cell population caused a delay in corneal wound healing, whereas supplementation of ILC2s through adoptive transfer partially restored the healing process. Further investigation revealed that IL-25, IL-33, and thymic stromal lymphopoietin had critical roles in corneal ILC2 responses and that CCR2- corneal macrophages were an important producer of IL-33 in the cornea. Together, these results reveal the critical role of cornea-resident ILC2s in the restoration of corneal epithelial integrity after acute injury and suggest that ILC2 responses depend on local induction of IL-25, IL-33, and thymic stromal lymphopoietin.