Light regulated vascular development of the eye

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DESCRIPTION (provided by applicant): Light is an all-pervasive biological stimulus. Most light on our planet comes from the sun and this is closely reflected in the mechanisms of light response that have evolved. Whether it is the phototropism of a unicellular green alga, the circadian entrainment of plants or high-acuity vision in humans, light elicits a huge variety of biological responses that are of fundamental importance. In this application, we provide evidence that in the mouse (and thus, probably in the human) light is an important stimulus for eye development. Unexpectedly, we found that dark reared neonatal mice exhibit abnormal vascular development in which the regression of hyaloid vessels is retarded and the growth of retinal vessels is promiscuous. The same abnormal growth is observed in light reared mice lacking the photopigment melanopsin. We have strong preliminary evidence that the maldevelopment of the ocular vessels is associated with (1) changes in the retinal level of the neurotrophin BDNF, (2) increased neuron number, and (3) altered VEGF expression level via oxygen demand. Also, surprisingly, the maximal effect of dark rearing is found in pups raised in darkness from E16. Our Central Hypothesis is: Ocular development is regulated by a fetal light-melanopsin-BDNF pathway that regulates neuron number, VEGF expression, and ultimately, postnatal vascular patterning. We propose three experimental aims: (1) To establish whether light activation of the melanopsin pathway in the fetus is necessary and sufficient to regulate vascular development in the eye, (2) to determine how BDNF signaling integrates with light-dependent vascular development, and (3) to define the role of oxygen demand in the light response pathway.