title: Direct regulation of Pitx3 expression by Nurr1 in culture and in developing mouse midbrain.
abstract: Due to their correlation with major human neurological diseases, dopaminergic neurons are some of the most studied neuronal subtypes. Mesencephalic dopaminergic (mDA) differentiation requires the activation of a cascade of transcription factors, among which play a crucial role the nuclear receptor Nurr1 and the paired-like homeodomain 3, Pitx3. During development the expression of Nurr1 precedes that of Pitx3 and those of typical dopaminergic markers such as tyrosine hydroxylase (TH) and dopamine Transporter (DAT) that are directly regulated by Nurr1. Interestingly we have previously demonstrated that Nurr1 RNA silencing reduced Pitx3 transcripts, leading to the hypothesis that Nurr1 may control Pitx3 expression.Here we show that Nurr1 overexpression up-regulates that of Pitx3 in a dose-dependent manner by binding to a non-canonical NBRE consensus sequence, located at the 5' site of the gene. Interestingly, this sequence shows the same effect as the canonical one in promoting gene translation, and its deletion abolishes the ability of Nurr1 to sustain reporter gene expression. Moreover, we show that there is a direct interaction between Nurr1 and the Pitx3 gene promoter in dopaminergic cell cultures and midbrain embryonic tissue. Altogether, our results suggest that the regulation of Pitx3 by Nurr1 may be an essential event controlling the development and function of mDA neurons.
authors.affiliation: Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Naples Italy.
authors.forename: Floriana
authors.initials: F
authors.lastname: Volpicelli
authors.forename: Roberto
authors.initials: R
authors.lastname: De Gregorio
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pulcrano
authors.forename: Carla
authors.initials: C
authors.lastname: Perrone-Capano
authors.forename: Umberto
authors.initials: U
authors.lastname: di Porzio
authors.forename: Gian Carlo
authors.initials: GC
authors.lastname: Bellenchi
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008636:Mesencephalon / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; C433629:homeobox protein PITX3