Retinoic acid regulates the expression of photoreceptor transcription factor NRL
Retinoic acid regulates the expression of photoreceptor transcription factor NRL
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DOI：
10.1074/jbc.m605500200
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发表时间：
2006-09-15
影响因子：
4.8
通讯作者：
Swaroop, Anand
中科院分区：
文献类型：
--
作者：
Khanna, Hemant;Akimoto, Masayuki;Swaroop, Anand
NRL（神经视网膜亮氨酸拉链）是一种关键的基本基序亮氨酸拉链（bZIP）转录因子，它通过激活视杆细胞特异性基因的表达来协调视杆细胞感光细胞的分化。小鼠中 Nrl 的缺失会产生源自视杆细胞前体的功能性视锥细胞。然而，调节 NRL 表达或活性的信号通路尚未阐明。在这里，我们发现视黄酸（RA）是一种与视杆细胞发育有关的扩散因子，在去血清的 Y79 人视网膜母细胞瘤细胞以及大鼠和猪光感受器的原代培养物中激活 NRL 的表达。 RA 的作用是由 RA 受体激动剂 TTNPB 模拟的，并且需要新的蛋白质合成。使用牛视网膜核提取物进行的 DNaseI 足迹分析和电泳迁移率变动分析 (EMSA) 表明，在 Nrl 启动子内鉴定出的 RA 反应元件 (RARE) 与 RA 受体结合。此外，在瞬时转染的 Y79 和 HEK293 细胞中，驱动荧光素酶报告基因的 Nrl 启动子的活性是由 RA 诱导的，并且这种激活是由 RARE 介导的。我们的数据表明，RA 信号通过 RA 受体调节 NRL 的表达，为描绘感光细胞命运决定的早期步骤提供了一个框架。
NRL (neural retina leucine zipper) is a key basic motif-leucine zipper (bZIP) transcription factor, which orchestrates rod photoreceptor differentiation by activating the expression of rod-specific genes. The deletion of Nrl in mice results in functional cones that are derived from rod precursors. However, signaling pathways modulating the expression or activity of NRL have not been elucidated. Here, we show that retinoic acid ( RA), a diffusible factor implicated in rod development, activates the expression of NRL in serum-deprived Y79 human retinoblastoma cells and in primary cultures of rat and porcine photoreceptors. The effect of RA is mimicked by TTNPB, a RA receptor agonist, and requires new protein synthesis. DNaseI footprinting and electrophoretic mobility shift assays ( EMSA) using bovine retinal nuclear extract demonstrate that RA response elements (RAREs) identified within the Nrl promoter bind to RA receptors. Furthermore, in transiently transfected Y79 and HEK293 cells the activity of Nrl-promoter driving a luciferase reporter gene is induced by RA, and this activation is mediated by RAREs. Our data suggest that signaling by RA via RA receptors regulates the expression of NRL, providing a framework for delineating early steps in photoreceptor cell fate determination.