Midbrain dopaminergic (mDA) neurons critically control voluntary movement, reward, and mood-related behaviors, and their degeneration/dysfunction is associated with major brain disorders such as Parkinson's disease (PD) and schizophrenia. Thus, it is critical to understand molecular mechanisms underlying development, survival, and function of mDA neurons in health and disease. During the last funding cycle, we investigated the regulatory networks of key extrinsic factors and intrinsic transcription factors that critically control mDA neuronal development, focusing on the role and regulation of Pitx3. We found that Wnt1-Lmx1a form an autoregulatory pathway leading to induction of key transcription factors, Nurr1 and Pitx3. Notably, these studies revealed that two major pathways controlling mDA neuronal development (i.e., Shh-FoxA2 and Wnt1-Lmx1a) merge on Nurr1, highlighting Nurr1's essential role(s) for mDA neuron development/ maintenance. Indeed, recent studies showed that Nurr1 is critical not only for the development and long-term maintenance of mDA neurons (by transactivation function) but also for their protection from inflammation-induced death (through transrepression of inflammatory genes). Nurr1 is an orphan nuclear receptor and is known as a ligand-independent constitutively active nuclear receptor. Strikingly, however, we recently identified small molecules that can directly interact with the ligand binding domain of Nurr1 stimulating its contrasting dual functions; furthe activating the mDA neuronal function and further transrepressing expression of inflammatory genes in microglia. Based on these promising data identifying potential synthetic ligands/agonists of Nurr1, we hypothesize that Nurr1 may be an adopted nuclear receptor and that there may exist an endogenous Nurr1 ligand. Furthermore, Nurr1's diverse functions (e.g., transactivation, transrepression, or no apparent function) appear to depend upon the cellular context, which may be determined by cell-specific Nurr1-interacting factor(s). To address these hypotheses, we will systematically investigate the contrasting dual functions of Nurr1 in the absence and in the presence of agonist molecules and will identify and characterize multiprotein complexes associated with Nurr1 in different cellular contexts and the putative endogenous ligand(s). Our proposal is highly novel and innovative and will shed new insights into the functional roles of Nurr1 in mDA neurons, potentially leading to a paradigm-shift of our understanding of Nurr1's functional roles on mDA neurobiology and future therapeutic development of DA-related brain disorders.
Midbrain dopamine (mDA) neurons play critical roles in the regulation of voluntary movement, emotion, and reward-related behavior, and their degeneration and/or dysfunction are associated with major brain disorders such as Parkinson's disease (PD), schizophrenia, and drug addiction. Based on our recent data identifying small molecules that can interact with the ligand binding domain of the orphan nuclear receptor Nurr1 leading to its activation, we will systematically investigate the contrasting dual functions of Nurr1 in the absence and in the presence of agonist molecules and identify and characterize the 'putative' endogenous ligand. Our proposal is highly novel and innovative and, if successfully done, will potentially lead to a paradigm shift of our understanding of Nurr1's functional roles on mDA neurobiology and future therapeutic development of DA- related brain disorders.
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