Abstract
Retinal ganglion cells send visual and circadian information to the brain regarding the environmental light-dark cycles. We investigated the capability of retinal ganglion cells of synthesizing melatonin, a highly reliable circadian marker that regulates retinal physiology, as well as the capacity of these cells to function as autonomous circadian oscillators. Chick retinal ganglion cells presented higher levels of melatonin assessed by radioimmunoassay during both the subjective day in constant darkness and the light phase of a light-dark cycle. Similar changes were observed in mRNA levels and activity of arylalkylamine N-acetyltransferase, a key enzyme in melatonin biosynthesis, with the highest levels of both parameters during the subjective day. These daily variations were preceded by the elevation of cyclic-AMP content, the second messenger involved in the regulation of melatonin biosynthesis. Moreover, cultures of immunopurified retinal ganglion cells at embryonic day 8 synchronized by medium exchange synthesized a [3H]melatonin-like indole from [3H]tryptophan. This [3H]indole was rapidly released to the culture medium and exhibited a daily variation, with levels peaking 8 h after synchronization, which declined a few hours later. Cultures of embryonic retinal ganglion cells also showed self-sustained daily rhythms in arylalkylamine N-acetyltransferase mRNA expression during at least three cycles with a period near 24 h. These rhythms were also observed after the application of glutamate. The results demonstrate that chick retinal ganglion cells may function as autonomous circadian oscillators synthesizing a melatonin-like indole during the day.
Highlights
In vertebrates, the circadian system that controls many physiological and behavioral rhythms includes the retina, which is responsible for photoreception and for synchronizing endogenous clocks to environmental lighting conditions [1,2,3,4,5,6,7]
In PRCs, arylalkylamine Nacetyltransferase (AA-NAT) mRNA levels exhibited a significant increase around midnight, peaking at zeitgeber times (ZTs) 19 –20 (Fig. 3A), whereas in Retinal ganglion cells (RGCs), levels of AA-NAT transcripts were elevated during the day over those observed at night (Fig. 3B)
Our results show that there is a significant daily variation of AA-NAT expression in RGCs, with mRNA levels at ZT 3 significantly higher than those found at all other time points studied
Summary
The circadian system that controls many physiological and behavioral rhythms includes the retina, which is responsible for photoreception and for synchronizing endogenous clocks to environmental lighting conditions [1,2,3,4,5,6,7]. Cultures of immunopurified retinal ganglion cells at embryonic day 8 synchronized by medium exchange synthesized a [3H]melatonin-like indole from [3H]tryptophan.
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