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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.

Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1.