title: Lmx1a is an activator of Rgs4 and Grb10 and is responsible for the correct specification of rostral and medial mdDA neurons.
abstract: The LIM homeodomain transcription factor Lmx1a is a very potent inducer of stem cells towards dopaminergic neurons. Despite several studies on the function of this gene, the exact in vivo role of Lmx1a in mesodiencephalic dopamine (mdDA) neuronal specification is still not understood. To analyse the genes functioning downstream of Lmx1a, we performed expression microarray analysis of LMX1A-overexpressing MN9D dopaminergic cells. Several interesting regulated genes were identified, based on their regulation in other previously generated expression arrays and on their expression pattern in the developing mdDA neuronal field. Post analysis through in vivo expression analysis in Lmx1a mouse mutant (dr/dr) embryos demonstrated a clear decrease in expression of the genes Grb10 and Rgs4, in and adjacent to the rostral and dorsal mdDA neuronal field and within the Lmx1a expression domain. Interestingly, the DA marker Vmat2 was significantly up-regulated as a consequence of increased LMX1A dose, and subsequent analysis on Lmx1a-mutant E14.5 and adult tissue revealed a significant decrease in Vmat2 expression in mdDA neurons. Taken together, microarray analysis of an LMX1A-overexpression cell system resulted in the identification of novel direct or indirect downstream targets of Lmx1a in mdDA neurons: Grb10, Rgs4 and Vmat2.
authors.affiliation: Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Elisa J
authors.initials: EJ
authors.lastname: Hoekstra
authors.forename: Lars
authors.initials: L
authors.lastname: von Oerthel
authors.forename: Annemarie J A
authors.initials: AJ
authors.lastname: van der Linden
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Schellevis
authors.forename: Gerard
authors.initials: G
authors.lastname: Scheppink
authors.forename: Frank C P
authors.initials: FC
authors.lastname: Holstege
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Groot-Koerkamp
authors.forename: Lars P
authors.initials: LP
authors.lastname: van der Heide
authors.forename: Marten P
authors.initials: MP
authors.lastname: Smidt
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism*; D051383:GRB10 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C495959:Grb10 protein, mouse; D060850:LIM-Homeodomain Proteins; C489692:Lmx1a protein, mouse; D020710:RGS Proteins; C493453:Slc18a2 protein, mouse; D014157:Transcription Factors; D050493:Vesicular Monoamine Transport Proteins; D051383:GRB10 Adaptor Protein; C098799:RGS4 protein