title: Specificity of Pitx3-Dependent Gene Regulatory Networks in Subsets of Midbrain Dopamine Neurons.
abstract: Dysfunction of midbrain dopaminergic (mDA) neurons is involved in Parkinson's disease (PD) and neuropsychiatric disorders. Pitx3 is expressed in mDA neuron subsets of the substantia nigra compacta (SNc) and of the ventral tegmental area (VTA) that are degeneration-sensitive in PD. The genetic network(s) and mode(s) of action of Pitx3 in these mDA neurons remain poorly characterized. We hypothesized that, given their distinct neuronal identities, Pitx3-expressing neurons of SNc and VTA should differ in their Pitx3-controlled gene expression networks and this may involve subset-specific co-regulators. Expression profiling of purified mDA neuronal subsets indicates that Pitx3 regulates different sets of genes in SNc and VTA, such as activating the expression of primary cilium gene products specifically in VTA neurons. Interaction network analysis pointed to the participation of differentially expressed Lhx/Lmo family members in the modulation of Pitx3 action in SNc and VTA mDA neurons. Conversely, global binding patterns of Pitx3 on genomic DNA of human dopaminergic cells revealed that Pitx3 is often co-recruited to regions that foster the formation of GATA-bHLH-BRN complexes, which usually involve Lmo co-regulatory proteins. We focused on Lmo3 for its preferential expression in SNc neurons and demonstrated that it functions as a transcriptional co-activator of Pitx3 by enhancing its activity on genomic regulatory elements. In summary, we defined the SN and VTA-specific programs of Pitx3-dependent gene expression and identified Lmo3 as a SN-specific co-regulator of Pitx3-dependent transcription.
authors: Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7, Canada.|Division of Experimental Medicine, McGill University, Montréal, Quebec, H3A 1A3, Canada.
authors: Panojot
authors: P
authors: Bifsha
authors: Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7, Canada.
authors: Aurelio
authors: A
authors: Balsalobre
authors: Laboratoire de génétique moléculaire, Institut de recherches cliniques de Montréal (IRCM), 110, avenue des Pins Ouest, Montréal, Québec, H2W 1R7, Canada. jacques.drouin@ircm.qc.ca.|Division of Experimental Medicine, McGill University, Montréal, Quebec, H3A 1A3, Canada. jacques.drouin@ircm.qc.ca.
authors: Jacques
authors: http://orcid.org/0000-0001-8226-5691
authors: J
authors: Drouin
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000235:genetics* / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics*; D008636:Mesencephalon / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D017557:Ventral Tegmental Area / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3; D004298:Dopamine
keywords: Lmo3; Parkinson; Primary cilium; Substantia nigra; Ventral tegmental area