Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1
Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1
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DOI：
10.1101/gad.1413606
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发表时间：
2006-05-15
影响因子：
10.5
通讯作者：
Evans, Ronald M.
中科院分区：
文献类型：
--
作者：
Zhang, Chun-Li;Zou, Yuhua;Evans, Ronald M.
在哺乳动物胚胎发生过程中，祖细胞增殖和分化的精确协调对于适当的器官大小和功能至关重要。 TLX (NR2EI)（一种孤儿核受体）的参与与眼部发育有关，因为 Tlx(-/-) 小鼠表现出视力障碍。通过遗传和生化方法，我们发现 TLX 通过直接调节 Pten 及其靶标细胞周期蛋白 D1 的表达来调节视网膜祖细胞增殖和细胞周期再进入。此外，TLX 通过调节磷脂酶 C 和丝裂原激活蛋白激酶 (MAPK) 途径以及一系列细胞类型特异性转录调节因子的表达来微调祖细胞分化程序。因此，Tlx(-/-) 小鼠的视网膜厚度显着减少，S 锥体的生成增加，并出现严重的早发性视网膜营养不良。此外，TLX 与肌萎缩蛋白 1 (Atn1) 相互作用，肌萎缩蛋白 1 是一种辅抑制因子，参与人类神经退行性齿状核红斑-苍白球路易体萎缩 (DRPLA)，对多种组织的发育至关重要。总之，这些结果揭示了一种分子策略，通过该策略，孤儿核受体可以精确地协调组织特异性增殖和分化程序，以防止视网膜畸形和变性。
During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2EI), an orphan nuclear receptor, has been implicated in ocular development, as Tlx(-/-) mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx(-/-) mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration.