In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development
In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development
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DOI：
10.1093/hmg/ddl185
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发表时间：
2006-09-01
影响因子：
3.5
通讯作者：
Swaroop, Anand
中科院分区：
文献类型：
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作者：
Cheng, Hong;Aleman, Tomas S.;Swaroop, Anand
哺乳动物视网膜中的视杆感受器和视锥感受器是由共同的神经上皮祖细胞池(S)产生的。NRL、CRX和NR2E3是控制光感受器分化的关键转录调控因子。杆状特异性孤儿核受体NR2 E3的突变导致视杆细胞丢失，S视锥细胞密度增加，S视锥细胞介导的视力异常。为了更好地了解其在体内的功能，NR2E3在NRL(-/-)视网膜异位表达，有丝分裂后的前体注定是杆状细胞，发育成类似于人类NR2E3疾病的功能性S锥体。NRL(-/-)视网膜中NR2E3的表达完全抑制视锥细胞的分化，并导致形态上的杆状感光细胞，但这些感光细胞并不起作用。FACS纯化的光感受器的基因图谱证实了NR2E3在体内作为视锥基因的强抑制者而仅激活视杆基因(包括视紫红质)的子集的作用。NR2 E3在视锥前体细胞中的异位表达和野生型视网膜的S视锥分化也产生了杆状细胞。NR2E3的双重调节功能不依赖于NRL和/或CRX的存在，而取决于其表达的时机和水平。我们的研究揭示了NR2E3在建立表达NRL的光感受器前体在视网膜神经发生过程中的功能特异性方面发挥了关键作用。
Rod and cone photoreceptors in mammalian retina are generated from common pool(s) of neuroepithelial progenitors. NRL, CRX and NR2E3 are key transcriptional regulators that control photoreceptor differentiation. Mutations in NR2E3, a rod-specific orphan nuclear receptor, lead to loss of rods, increased density of S-cones and supernormal S-cone-mediated vision in humans. To better understand its in vivo function, NR2E3 was expressed ectopically in the Nrl(-/-) retina, where post-mitotic precursors fated to be rods develop into functional S-cones similar to the human NR2E3 disease. Expression of NR2E3 in the Nrl(-/-) retina completely suppressed cone differentiation and resulted in morphologically rod-like photoreceptors, which were however not functional. Gene profiling of FACS-purified photoreceptors confirmed the role of NR2E3 as a strong suppressor of cone genes but an activator of only a subset of rod genes (including rhodopsin) in vivo. Ectopic expression of NR2E3 in cone precursors and differentiating S-cones of wild-type retina also generated rod-like cells. The dual regulatory function of NR2E3 was not dependent upon the presence of NRL and/or CRX, but on the timing and level of its expression. Our studies reveal a critical role of NR2E3 in establishing functional specificity of NRL-expressing photoreceptor precursors during retinal neurogenesis.