Analyzing the function of nuclear receptor Nor-1 in mice

Abstract

Nuclear receptor Nor-1, together with Nur77 and Nurr1, belongs to the NR4A subfamily of nuclear receptors. Human Nor-1 protein was identified in a chromosomal translocation in extraskeletal myxoid chondrosarcoma. This suggests that Nor-1 may play a role in chondrocyte proliferation. The precise role of Nor-1 in mammalian development has not been previously established. Therefore, to examine the spatiotemporal expression pattern of nor-1 and the physiological consequences of nor-1 ablation, nor-1 knock-out mice were generated by insertion of the lacZ gene into the nor-1 genomic locus. Despite nor-1 expression during chondrocyte development, no defect in the outgrowth of the skeleton was detected in nor-1-/- mice. However, disruption of the nor-1 gene resulted in a partial bidirectional circling phenotype in the adult mice. The circling behavior can be explained by a defect in the proliferative continual growth of the semicircular canals. The semicircular canals are a part of the vestibular system of the inner ear, a structure responsible for maintaining balance. Nor-1 was also essential for the development of the murine hippocampus; in the absence of Nor-1 the CA3 pyramidal cell layer was dispersed. This was accompanied by a loss of a subset of cells in the CA1 field. In addition, postnatal axonal growth of the dentate gyrus granule cell and mossy cell axons was reduced. These developmental defects in the hippocampus resulted in seizure susceptibility to a convulsant kainic acid in the adult nor-1-/- mice. Behavioral testing revealed that nor-1-/- mice also suffered from heightened fear. Examination of the mediators in the inflammatory pathway suggested Nurr1, and not Nor-1 or Nur77 involvement in the pathogenesis of rheumatoid arthritis. Taken together, the NR4A family members may have both shared and specific functions.