Regulation Of Tph And Aanat Expression Andactivity

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3.1. Localization of TPH and AA-NAT mRNAs in Retina

AA-NAT mRNA is localized primarily to the photoreceptor layer of the chick retina, with a lower level of expression in the ganglion cell layer (2); expression was not detected in the inner nuclear layer. TPH mRNA expression is also strong in the photoreceptor layer (12). In addition, TPH mRNA is found in the ganglion cell and inner nuclear layers. The localization of TPH mRNA alone (without AA-NAT mRNA) in the inner nuclear layer corresponds to the previously described serotonin-immunoreactive amacrine cells (28,39). Expression of both mRNAs in photoreceptors is consistent with this cell type as the primary source of retinal melatonin.

Localization of TPH and AA-NAT mRNAs in the ganglion cell layer is unexpected, as serotonin immunoreactivity has not been observed in this cell layer of chick retina. This observation suggests that some ganglion cells may synthesize melatonin or N-acetylserotonin. However, the available evidence suggests that melatonin synthesis in ganglion cells is not significant relative to that formed in photoreceptor cells. This is because destruction of most ganglion cells by kainic acid does not decrease melatonin production nor damage photoreceptor cells (39).

3.2. Circadian Rhythms of TPH and AA-NAT mRNAs and Activities

The daily rhythms of TPH and AA-NAT activities are very similar in retinas of chicks exposed to a 12h light—12h dark cycle (LD) (Figure 1). Activities of both enzymes are low during the day and show robust increases early in the dark phase of the light-dark cycle. These rhythms of activity appear to be generated, at least in part, by rhythmic expression of TPH and AA-NAT mRNAs (2,12). The daily rhythms of mRNA level and activity are driven by a circadian oscillator and persist in constant light (LL) and constant darkness (DD). The rhythms of mRNA level under constant conditions are very similar for both enzymes, showing peaks in the middle of the subjective dark phase. Thus, expression of the TPH and AA-NAT genes may be regulated by the same clock driven mechanism.

In DD, the rhythms of TPH activity and NAT activity are similar to one another and appear to reflect the expression patterns of their respective mRNAs (2,12,38). In LL, high amplitude TPH activity rhythms occur (Figure 2). Nocturnal activity is only slightly reduced on the first day of LL, but gradually declines over successive days. LL has similar effects on the pattern of TPH mRNA expression (12). In contrast, AA-NAT activity is greatly suppressed (~85%) at night in LL, resulting in a markedly reduced amplitude of the daily rhythm (Figs. 2, 3). The amplitude of the AA-NAT mRNA rhythm is also reduced, but to a much smaller extent (~50%) (Figure 3). This observation indicates that light has a suppressive effect on AA-NAT activity, but not on TPH activity, that may reflect differences in post-transcriptional regulation.

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