Biliverdin regulates NR2E3 and zebrafish retinal photoreceptor development.

NR2E3 is an orphan nuclear receptor whose loss-of-function causes abnormal retinal photoreceptor development and degeneration. However, despite that many nuclear receptors are regulated by binding of small molecule ligands, biological small molecule ligands regulating NR2E3 have not been identified. Identification of an endogenous NR2E3 ligand might reveal a previously unrecognized component contributing to retinal development and maintenance. Here we report that biliverdin, a conserved green pigment from heme catabolism, regulates NR2E3 and is necessary for zebrafish retinal photoreceptor development. Biliverdin from retinal extracts specifically bound to NR2E3’s ligand-binding domain and induced NR2E3-dependent reporter gene expression. Inhibition of biliverdin synthesis decreased photoreceptor cell populations in zebrafish larvae, and this phenotype was alleviated by exogenously supplied biliverdin. Thus, biliverdin is an endogenous small molecule ligand for NR2E3 and a component necessary for the proper development of photoreceptor cells. This result suggests a possible role of heme metabolism in the regulation of retinal photoreceptor cell development.

NR2E3是一种孤儿核受体，其功能缺失会导致视网膜光感受器发育异常和退化。然而，尽管许多核受体受小分子配体结合的调控，但调节NR2E3的生物小分子配体尚未被确定。内源性NR2E3配体的确定可能揭示一种之前未被认识的、对视网膜发育和维持有贡献的成分。在此我们报道，胆绿素——一种来自血红素分解代谢的保守绿色色素，可调节NR2E3，并且对斑马鱼视网膜光感受器发育是必需的。来自视网膜提取物的胆绿素特异性结合到NR2E3的配体结合域，并诱导依赖于NR2E3的报告基因表达。抑制胆绿素合成会减少斑马鱼幼体中的光感受器细胞数量，而外源性提供胆绿素可缓解这种表型。因此，胆绿素是NR2E3的一种内源性小分子配体，也是光感受器细胞正常发育所必需的成分。这一结果提示血红素代谢在视网膜光感受器细胞发育的调控中可能具有的作用。