Transcription factor control in neuronal maintenance and survival

The Transcription factor (TF) Nurr1 is essential for the development of a group of dopamine neurons that are located in the ventral midbrain (also referred to as mesencephalon). A progressive pathology of these midbrain dopamine (mDA) neurons is evident in Parkinson s disease, the most frequent neurodegenerative movement disorder. In addition Nurr1 is expressed in a number of other CNS areas. In the hippocampus, Nurr1 is co-expressed with its homologues Nur77 and Nor1, collectively named for NR4A TF s. These TF s are rapidly and strongly induced in response to stressful stimuli and an acute NR4A induction has been noted in e. g. hippocampal, cortical and striatal neurons after ischemia, seizures and focal brain injury in rodents. However, the functional roles of the stress-induced NR4A-expression have remained unknown. As Nurr1 is critical for the mDA neuron development and is widely expressed in the adult CNS, we hypothesized that Nurr1 might also play a crucial role in maintaining mature neurons. To address this hypothesis, the functional consequences of gain-of-function or loss-of-function of NR4A proteins were assessed in maturing and adult neurons in vitro and in vivo. The research presented in paper I & II describes the consequences of spatiotemporal ablation of Nurr1 in mDA neurons in mice. Our results revealed that Nurr1 continues to be critical for the maturing mDA neurons and for maintaining a DA phenotype in the mDA neurons of adult mice. In paper III, the function of stress-induced NR4A proteins was characterized in vitro in cultured neurons and in vivo in the hippocampi of mice. The data revealed that stress-induced NR4A promoted neuroprotection in neurons, presumably by up-regulating a subset of neuroprotective genes. The work in paper IV deals with the mechanism by which Nurr1 mediates transcriptional activation. We identified a novel putative Nurr1 coregulator-binding site that might recruit as yet unknown coregulators.

List of scientific papers

I. Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S, Sumi-Ichinose C, Nomura T, Metzger D, Chambon P, Lindqvist E, Larsson NG, Olson L, Björklund A, Ichinose H, Perlmann T (2009). "Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons." J Neurosci. 29(50):15923-32.
https://pubmed.ncbi.nlm.nih.gov/20016108

II. Kadkhodaei B, Perlmann T (2010). "Maintenance of midbrain dopaminergic neurons." [Manuscript]

III. Volakakis N, Kadkhodaei B, Joodmardi E, Wallis K, Vennström B, Spiegelman BM, Perlmann T (2010). "NR4A orphan nuclear receptors trigger a neuroprotective pathway induced by elevated cyclic AMP." [Manuscript]

IV. Volakakis N, Malewicz M, Kadkhodai B, Perlmann T, Benoit G (2006). "Characterization of the Nurr1 ligand-binding domain co-activator interaction surface." J Mol Endocrinol. 37(2): 317-26.
https://pubmed.ncbi.nlm.nih.gov/17032747