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GTP Cyclohydrolase I Gene Expression in the Brains of Male and Female hph‐1 Mice
Author(s) -
Shimoji Mika,
Hirayama Kei,
Hyland Keith,
Kapatos Gregory
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0720757.x
Subject(s) - gtp cyclohydrolase i , gene expression , gene , endocrinology , medicine , gtp' , biology , messenger rna , microbiology and biotechnology , genetics , biochemistry , enzyme , nitric oxide synthase , nitric oxide , tetrahydrobiopterin
: The hph‐1 mouse is characterized by low levelsof GTP cyclohydrolase I (GTPCH) and tetrahydrobiopterin. A quantitativedouble‐lable in situ hybridization technique was used to examine CNS GTPCHmRNA expression within serotonin, dopamine, and norepinephrine neurons of maleand female wild‐type and hph‐1 mice. In wild‐type male and femaleanimals the highest levels of GTPCH mRNA expression were observed withinserotonin neurons, followed by norepinephrine and then dopamine neurons.Wild‐type female animals were found to express lower levels of GTPCH mRNA ineach cell type when compared with levels seen in wild‐type males. GTPCH mRNAabundance in all three cell types was lower in hph‐1 male than inwild‐type male mice, with the greatest reduction in serotonin neurons. GTPCHmRNA levels were also lower in hph‐1 female than in wild‐type femalemice, again with the greatest reduction occurring in serotonin neurons.Comparison of hph‐1 male and hph‐1 female mice revealed thatthe sex‐linked difference in GTPCH mRNA expression observed in wild‐typeneurons was only present within female dopamine neurons. Overall, theseresults indicate that not only are basal levels of GTPCH mRNA expressionheterogeneous across wild‐type murine monoamine cell types but that geneexpression is also modified in a sex‐linked and cell‐specific fashion by the hph‐1 gene locus. The hph‐1 mutation does not lie within theGT‐PCH mRNA coding region. The 5′ flanking region of the GTPCH gene wascloned and sequenced and shown to be identical for both wild‐type and hph‐1 genomic DNA. Transient transfection assays performed in PC12cells demonstrated that this 5′ flanking region was sufficient toinitiate transcription of a luciferase reporter gene. Although the hph‐1 mutation does not lie within the 5′ flanking region of the GTPCH gene, this region of the gene can function as a core promoter and is thus crucial to the control of GTPCH gene expression.