Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1.
Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1.
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DOI：
10.1210/mend.10.12.8961274
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发表时间：
1996-12
影响因子：
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通讯作者：
R. Zetterström;L. Solomin;T. Mitsiadis;L. Olson;T. Perlmann
中科院分区：
文献类型：
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作者：
R. Zetterström;L. Solomin;T. Mitsiadis;L. Olson;T. Perlmann
NGFI-B、Nurr1和Nor1是类固醇/甲状腺激素受体超家族中三个关系密切的孤儿成员。这些受体可以作为单体与DNA结合，并表现出结构性转录活性。此外，其中两个受体，NGFI-B和Nurr1，先前已被证明与维甲酸X受体(RXR)形成异二聚体。这种异源二聚体以及RXR和全反式维甲酸受体之间形成的复合体与DNA反应元件结合，这些DNA反应元件由五个核苷酸(DR5)组成的直接重复序列组成。然而，维甲酸受体可以抑制配体依赖的RXR激活，而NGFI-B和Nurr1则通过DR5元件有效地激活RXR，从而定义了一条不同的维生素A信号转导途径。在这项研究中，我们证明了最近发现的亚家族成员Nor1与NGFI-B和Nurr1具有相似的单体DNA结合和结构性反式激活特性。相反，Nor1不能促进RXR信号转导，因为它不能与RXR形成异二聚体。为了开始了解这些功能差异的生理意义，我们使用原位杂交来比较Nor1、NGFI-B和Nurr1信使RNA在不同发育阶段的分布。受体以不同的和重叠的模式表达，主要在中枢神经系统。值得注意的是，Nurr1在产前腹侧中脑中的一个区域表达，该区域产生多巴胺能神经元。Nor1在胚胎发育过程中也有表达，这三种受体在出生后的大脑中都表现出复杂的分布。此外，Nor1与NGFI-B共存于肾上腺和胸腺，这两个组织中NGFI-B被认为具有重要的功能。这些数据可能表明NGFI-B/Nurr1/Nor1亚家族成员之间存在冗余，并可以解释为什么在NGFI-B基因失活的小鼠中尚未发现表型障碍。
NGFI-B, Nurr1, and Nor1 are three closely related orphan members of the steroid/thyroid hormone receptor superfamily. These receptors can bind to DNA as monomers and exhibit constitutive transcriptional activity. Moreover, two of the receptors, NGFI-B and Nurr1, have previously been shown to form heterodimers with the retinoid X receptor (RXR). Such heterodimers as well as complexes formed between RXR and the all-trans retinoic acid receptor bind to DNA response elements composed of direct repeats spaced by five nucleotides (DR5). However, whereas retinoic acid receptor can inhibit ligand-dependent RXR activation, NGFI-B and Nurr1 allow efficient RXR activation through DR5 elements and thus define a distinct pathway for vitamin A signaling. In this study we demonstrate that the most recently identified member of the subfamily, Nor1, shows similar monomer DNA-binding and constitutive transactivation properties as NGFI-B and Nurr1. In contrast, however, Nor1 is unable to promote RXR signaling due to its inability to form heterodimers with RXR. To begin to understand the physiological implications of these functional differences we used in situ hybridization to compare the distribution of Nor1, NGFI-B, and Nurr1 messenger RNAs during different developmental stages. The receptors are expressed in both distinct and overlapping patterns, predominantly in the central nervous system. Notably, Nurr1 is expressed in the prenatal ventral midbrain in a region that gives rise to dopaminergic neurons. Nor1 is also expressed during embryonic development, and all three receptors show a complex distribution in the postnatal brain. Furthermore, Nor1 colocalizes with NGFI-B in the adrenal glands and thymus, two tissues in which NGFI-B has been suggested to be functionally important. These data may indicate redundancy between members of the NGFI-B/Nurr1/Nor1 subfamily and could explain why no phenotypic disturbances have yet been found in mice in which the NGFI-B gene has been inactivated.