title: Orphan nuclear receptor Nurr1 is essential for Ret expression in midbrain dopamine neurons and in the brain stem.
abstract: The orphan nuclear receptor Nurr1 is essential for development of midbrain dopamine (DA) cells. In Nurr1-deficient mice, DA precursor cells fail to migrate normally, are unable to innervate target areas, and only transiently express DA cell marker genes. In the search for Nurr1-regulated genes that might explain this developmental phenotype, we found that expression of the receptor tyrosine kinase Ret is deregulated in these cells of Nurr1-deficient embryos. In addition, our analyses establish Nurr1 as an early marker for the dorsal motor nucleus (DMN) of the vagus nerve. Interestingly, Ret expression is absent also in these cells in Nurr1-targeted mice. Neuronal innervation of vagus nerve target areas appeared normal apart from a subtle disorganization of the DMN-derived nerve fibers. In conclusion, regulation of Ret by Nurr1 in midbrain DA neurons and in the DMN has implications for both embryonal development and adult physiology in which signaling by neurotrophic factors plays important roles.
authors.affiliation: Ludwig Institute for Cancer Research, Karolinska Institutet, S-171 77 Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Wallén A
authors.forename: D S
authors.initials: DS
authors.lastname: Castro
authors.forename: R H
authors.initials: RH
authors.lastname: Zetterström
authors.forename: M
authors.initials: M
authors.lastname: Karlén
authors.forename: L
authors.initials: L
authors.lastname: Olson
authors.forename: J
authors.initials: J
authors.lastname: Ericson
authors.forename: T
authors.initials: T
authors.lastname: Perlmann
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins; D004298:Dopamine / Q000378:metabolism*; D029721:Drosophila Proteins; D005260:Female; D005333:Fetus; D005786:Gene Expression Regulation / Q000502:physiology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency* / Q000235:genetics; D050697:Retinal Dehydrogenase; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D014630:Vagus Nerve / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D014781:Viscera / Q000196:embryology / Q000294:innervation
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D026901:Membrane Transport Proteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C493460:Slc18a3 protein, mouse; D014157:Transcription Factors; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D000445:Aldehyde Oxidoreductases; D050697:Retinal Dehydrogenase; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D000110:Acetylcholinesterase; D004298:Dopamine