title: Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles.
abstract: We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock-in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK-2 or BMPR-II preceded by an internal ribosome entry site (IRES) were introduced into the 3' untranslated region of TH. An frt-flanked neomycin-resistance (neo(r)) cassette was placed in the 3' end of the targeting constructs. Mice homozygous for the knock-in alleles showed various degrees of hypokinetic behavior, depending mainly on whether the neo(r) cassette was removed. In situ hybridization and immunohistochemistry showed that TH mRNA and protein were variously down-regulated in these mouse strains. Reduced levels of dopamine and noradrenalin were found in several brain areas. However, number and morphology of neurons in substantia nigra and their projections to striatum appeared normal in the neo(r)-positive TH hypomorphic mice as examined by markers for L-aromatic amino acid decarboxylase and the dopamine transporter. Elimination of the neo(r) cassette from the knock-in alleles partially restored TH and dopamine levels. The present neo(r)-positive TH hypomorphic mice show that nigrostriatal innervation develops independently of TH and should find use as a model for conditions of reduced catecholamine synthesis, as seen in, for example, L-dihydroxyphenylalanine-responsive dystonia/infantile parkinsonism.
authors.affiliation: Department of Neuroscience, Unit of Developmental Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Althini
authors.forename: Henrik
authors.initials: H
authors.lastname: Bengtsson
authors.forename: Dmitry
authors.initials: D
authors.lastname: Usoskin
authors.forename: Stine
authors.initials: S
authors.lastname: Söderström
authors.forename: Annika
authors.initials: A
authors.lastname: Kylberg
authors.forename: Eva
authors.initials: E
authors.lastname: Lindqvist
authors.forename: Susana
authors.initials: S
authors.lastname: Chuva de Sousa Lopes
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.forename: Jonas
authors.initials: J
authors.lastname: Lindeberg
authors.forename: Ted
authors.initials: T
authors.lastname: Ebendal
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D004351:Drug Resistance; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D016254:Mutagenesis, Insertional; D009355:Neomycin; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011506:Proteins; D012333:RNA, Messenger / Q000032:analysis; D012701:Serotonin / Q000032:analysis / Q000378:metabolism; D013378:Substantia Nigra / Q000201:enzymology*; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011506:Proteins; D012333:RNA, Messenger; D012701:Serotonin; D014446:Tyrosine 3-Monooxygenase; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II; D009355:Neomycin; D004298:Dopamine; D009638:Norepinephrine