The mesencephalic dopaminergic (mesDA) system is involved in many brain functions including motor control and motivated behaviour, and is of clinical importance because of its implication in psychiatric disorders and Parkinson's disease. Nurr1, a member of the nuclear hormone receptor superfamily of transcription factors, is essential for establishing the dopaminergic phenotype, because expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis, requires Nurr1. In addition, Nurr1 plays an important role in the maintenance of mesDA neurons. Neonatal Nurr1 knockout mice lack expression of the dopamine transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and l-aromatic amino acid decarboxylase (AADC) in addition to TH specifically in mesDA neurons. It is unclear whether the lack of expression of these dopaminergic markers is caused by a maintenance defect or whether the induction of these markers depends on Nurr1 expression. To address this problem, the expression of DAT, VMAT2 and AADC was analysed at embryonic day 12.5 and 14.5. Here we demonstrate that induction of VMAT2 and DAT specifically in mesDA neurons requires Nurr1 expression, whereas AADC expression in mesDA neurons is induced independently of Nurr1 function.

Modulation of the NURR subfamily of nuclear receptors may be an important mechanism regulating pathways associated with inflammatory joint disease. We examined the signaling mechanisms through which inflammatory mediators, produced by rheumatoid arthritis (RA) synovial tissue, contribute to the regulation of the NURR subfamily. Markedly enhanced expression of NURR1 is observed in synovial tissue of patients with RA compared with normal subjects. Modulation by proinflammatory mediators in primary RA and normal synoviocytes shows that PGE2, IL-1β, and TNF-α markedly enhance NURR1 mRNA and protein levels in contrast to other subfamily members, NUR77 and NOR-1. We have established that transcriptional activation of the NURR1 gene by IL-1β and TNF-α requires a proximal promoter region that contains a consensus NF-κB DNA-binding motif. IL-1β- and TNF-α-induced NF-κB binding to this site is due predominantly to p65-p50 heterodimer and p50 homodimer subunit protein complexes. We further demonstrate a direct CREB-1-dependent regulation by PGE2 situated at promoter region −171/−163. Moreover, analyses confirm the presence of CREB-1 and NF-κB p50 and p65 subunit binding to the NURR1 promoter under basal conditions in freshly explanted RA synovial tissue. In summary, enhanced NF-κB- and CREB-1-binding activity on the NURR1 promoter by inflammatory mediators delineates novel mechanisms in the regulation of NURR1 transcription. PGE2-, TNF-α-, and IL-1β-dependent stimulation of the NURR1 gene implies that NURR1 induction represents a point of convergence of at least two distinct signaling pathways, suggesting an important common role for this transcription factor in mediating multiple inflammatory signals.

Nor-1 belongs to the nur subfamily of nuclear receptor transcription factors. The precise role of Nor-1 in mammalian development has not been established. However, recent studies indicate a function for this transcription factor in oncogenesis and apoptosis. To examine the spatiotemporal expression pattern of Nor-1 and the developmental and physiological consequences of Nor-1 ablation, Nor-1-null mice were generated by insertion of the lacZ gene into the Nor-1 genomic locus. Disruption of the Nor-1 gene results in inner ear defects and partial bidirectional circling behavior. During early otic development, Nor-1 is expressed exclusively in the semicircular canal forming fusion plates. After formation of the membranous labyrinth, Nor-1 expression in the vestibule is limited to nonsensory epithelial cells localized at the inner edge of the semicircular canals and to the ampullary and utricular walls. In the absence of Nor-1, the vestibular walls fuse together as normal; however, the endolymphatic fluid space in the semicircular canals is diminished and the roof of the ampulla appears flattened due to defective continual proliferative growth of the semicircular canals.The mouse inner ear develops during the second half of gestation from an otic epithelial vesicle that undergoes a complex series of shape changes to give rise to specific functional compartments including the cochlea, which comprises the auditory apparatus, and the vestibule, which is responsible for sensing motion and gravity. The endolymphatic fluid-filled membranous labyrinth is surrounded by perilymphatic fluid and is contained within an osseous structure (tympanic bone). The vestibular part of the inner ear contains two principal sets of sensory structures, the maculae (saccule and utricle), sensors of linear acceleration and gravity, and the cristae ampullaris, sensors of angular acceleration that are contained within three ampullae. Stimuli related to vestibular functions are produced by movement of the endolymphatic fluid and are recorded by sensory hair cells of the maculae and cristae.Development of the murine inner ear is initiated at E8.5 by the formation of an otic epithelial placode, which arises as a thickening of the head ectoderm between rhombomeres 5 and 6 in the hindbrain, followed by invagination and separation from the ectoderm to become a closed vesicle embedded in the head mesenchyme at E9.5. Structural perturbances begin to occur in the vesicle at E11 to 11.5 with the outgrowth of the ventral wall of the otic vesicle to form a hollow tube that gives rise to the cochlea and a dorsal extension that forms the endolymphatic duct. Cells localized in the dorsolateral walls give rise to the semicircular canals, while the medial and medioventral regions give rise to the utricle and saccule (38). Restricted and asymmetric expression patterns in the otic vesicle have been described for several genes (14, 38) at this developmental stage. These genes then participate in the regional morphogenesis of the inner ear.The semicircular canals or...

The nuclear receptor transcription factor, nor-1, is expressed during mammalian development predominantly in the nervous system and is induced in a cell-specific manner in nonneuronal cells in response to a variety of extracellular stimuli. To elucidate the essential developmental functions of this transcription factor, we have analyzed the consequences of its elimination on central nervous system development in mice. Here we show that null mutant mice lacking nor-1 respond with increased limbic seizure activity to the excitotoxic glutamate receptor agonist kainic acid. We demonstrate that these abnormalities are associated with defective postnatal hippocampal development exemplified by abnormal axonal guidance of dentate gyrus granule and mossy cells, disorganization of the pyramidal cell layer, and early postnatal death of pyramidal neurons in the CA1 field of the hippocampus. Our data indicate that nor-1 plays a critical role in neuronal survival and axonal guidance in the developing murine hippocampus and that hippocampal dysgenesis in nor-1 ؊/؊ mice may be an underlying cause of seizure susceptibility.nor-1 (NR4A3) is a member of the nuclear receptor family of transcription factors, whose developmental and physiological functions are poorly understood. nor-1 (NR4A3) and two highly homologous transcription factors, nurr1 (NR4A2) and nur77 (NR4A1), constitute the NR4A subfamily of nuclear receptors (2). Unlike most nuclear receptors, the regulator function of NR4A receptors is constitutively active and does not require ligand modulation (17,40,43). All three proteins are products of immediate-early genes whose transcription is rapidly induced in response to a variety of extracellular stimuli, including mitogens, apoptotic signals, and neurotransmitters (reviewed in reference 21). The induced nuclear receptors undergo site-specific phosphorylation to modulate their transcriptional activity (8,14,27) and bind to specific cis-acting DNA elements containing the sequence motif AAAGGTCA to regulate the expression of defined sets of target genes in a stimulus-and cell-specific manner (17,26,43).Previous studies have suggested that members of the NR4A subfamily of nuclear receptors, including nor-1, play key roles in mediating neuronal differentiation during central nervous system (CNS) development and in activity-dependent maintenance of neuronal plasticity in the adult CNS. For example, expression of nurr1 in the ventral midbrain is essential for embryonic specification of dopaminergic neurons (5, 33, 46). All three NR4A receptors are expressed in the limbic system, including hippocampal pyramidal neurons of the adult CNS (32, 47), suggesting a potential involvement in the regulation of long-term changes in gene expression associated with learning and memory. In addition, their expression is rapidly and transiently induced in both pyramidal neurons and dentate granule cells of the hippocampus in experimental animal models of temporal lobe epilepsy (TLE), including chemically and electrically induced limbic seizure ...