Some aspects of nuclear receptor function in the CNS : Novel roles of Nurr1 and RXR in developing and mature neurons

Abstract: The nuclear receptor superfamily comprises the receptors for steroid hormones, thyroid hormone, vitamin D and retinoids. The family also includes a number of receptors that lack identified ligands, and are therefore referred to as orphan receptors. The nuclear receptors function as ligand-activated transcription factors, and regulate expression of specific target genes. Expression of the orphan nuclear receptor Nurr1 (NR4A2) was previously shown to be abundant in the central nervous system (CNS) of the mouse and rat where it is detected from early embryogenesis into adulthood. Gene targeting of the Nurr1 gene leads to agenesis of midbrain dopamine (DA) neurons as initially shown by lack of DA cell- specific markers at birth. Midbrain DA neurons regulate motor control and their degeneration is the cause of Parkinson's disease. The Nurr1 mutant mice are born at expected frequency but die within the first day after birth. The present study aimed at understanding the fate of midbrain DA neurons in the absence of Nurr1 and to identify target genes of Nurr1 that mediate the function of this orphan receptor in DA neuron development. In addition to this, the role of Nurr1 in neonatal survival was examined. Furthermore, as Nurr1 is abundantly expressed in the CNS, not only during development but also in the adult rodent, it may be important for mature neurons, an issue that was also addressed in this study. Gene expression, innervation, cell migration and survival were analyzed in the ventral midbrain of Nurr1 mutant mice and are shown to be affected by the loss of Nurr1, thus explaining the absence of DA neurons in the newborn Nurr1 mutant animal. Expression of the receptor tyrosine kinase Ret is shown to be regulated by Nurr1, a feature which does not explain the loss of DA neurons in the Nurr1 mutant, but which may have implications for DA neuron function in the adult mouse. Another target gene identified in this study is the cyclin-dependent kinase inhibitor p57Kip2 . The expression of this gene is shown to be Nurr1-dependent, and analysis of p57Kip2 gene-targeted mice revealed a similar phenotype in the DA neurons as displayed in the Nurr1 mutant mice, demonstrating that p57Kip2 is required for normal DA cell development. The mechanism appears to involve direct protein-protein interaction where p57Kip2 acts as a cofactor for Nurr1 in mediating DA neuron differentiation. Respiration and response to hypoxia were analyzed in vivo and in vitro in the Nurr1 mutant pups and it is shown that loss of this orphan receptor results in severe hypoventilation and lack of response to hypoxia. The drastic disturbance in control of breathing is likely connected to abnormal function of respiratory nuclei in the brainstem and carotid bodies. The respiratory deficiency may be directly involved in the neonatal death of the Nurr1 mutant animals and might be related to the sudden infant death syndrome and congenital central hypoventilation syndrome in humans. Transgenic mice, tissue explants and primary CNS cultures were used to address the role of Nurr1 and the retinoid X receptor (RXR; NR2B1-3) in mature neurons. It is shown that these receptors are involved in mediating neuronal survival in response to RXR-specific ligands, so called rexinoids. Nurr1 and RXR are shown to act as neuroprotective factors for midbrain DA neurons as well as cortical and hippocampal neurons. Activating these receptors might thus achieve increased neuronal survival in treatment of disease, for example Parkinson's disease.