Melanopsin-mediated light responses in the embryonic retina

University Of California, San Francisco, San Francisco CA

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Abstract

? DESCRIPTION (provided by applicant): A separate non-rod, non-cone visual system is now known to exist and function in the retinas of most mammalian classes from mice to humans. This secondary system is comprised of a subset of retinal ganglion cells in the eye that express the photopigment melanopsin (mRGCs). In adults, activation of these mRGCs regulates photo entrainment of circadian rhythm and pupil constriction. Additionally, these mRGCs are thought to be involved in photophobia during migraine headaches and seasonal affective disorder (SAD). Surprisingly, melanopsin is expressed very early during embryonic development (gestational week 8 in humans and embryonic day (E) 11 in mice). These early born mRGCs are functional well before the maturation of vision that is mediated by the more conventional rods and cones. As evidence, light activation of mRGCs in young neonatal mice evokes photoaversion and vocalizations associated with stress. Moreover, a study of vascular development in mouse eye demonstrated that light exposure of fetuses in utero modulates the timing of angiogenic maturation in the eyes of the subsequently born pups. The effects of light require the expression of melanopsin in the fetal eye. Thus, this strongly suggests that melanopsin expressing cells in the fetal eye can be activated by light exposure and this activation, by signaling to other cells within the eye, modulates and triggers developmental vascular and neuronal programs. No studies to date have directly demonstrated light sensitive neurons in the embryonic retina. We have recent preliminary evidence directly proving that light can elicit responses in melanopsin-expressing neurons in embryonic retinas of mice as young as E16.5, 4 days before birth. One aim of this proposed project seeks to 1) characterize the kinetics and sensitivity of the light responses evoked in the embryonic mRGCs, and 2) to determine the ionic and pharmacological mechanisms of phototransduction in these same mRGCs. A second aim addresses intercellular signaling from mRGCs to other cells in the embryonic retina. Given that light activation of these embryonic mRGCs is coupled to pathways regulating vascular and neuronal development in the eye, it is imperative to understand by what means these signals are communicated to other cells in the embryonic retina. This is an important first step in elucidating downstream signaling that can regulate subsequent maturation. These experiments significantly extend the formerly classical concepts of when vision and light sensitivity become manifest in the maturing infant. Because melanopsin expression occurs very early in the human eye, an inference from our mouse studies would argue that premature infants between GW24 and 30 should exhibit melanopsin-mediated photoresponses in their retinas. This provides a basis to attend to photo aversive behavior and light-regulated circadian rhythms in very young, prematurely born infants.