RESUMO
Free D-aspartic acid and NMDA are present in the mammalian central nervous system and endocrine glands at significant concentrations, but their physiological role is still matter of debate. The only enzyme known to metabolize in vitro selectively these D-amino acids is D-aspartate oxidase (DDO). To clarify the role in vivo of the enzyme, we generated mice with targeted deletion of Ddo gene by homologous recombination. Mutated animals showed increased amounts of both D-aspartic acid and NMDA in all tissues examined demonstrating a physiological role of DDO in the regulation of their endogenous levels.
Assuntos
D-Aspartato Oxidase/deficiência , Ácido D-Aspártico/fisiologia , Regulação Enzimológica da Expressão Gênica , N-Metilaspartato/fisiologia , Animais , D-Aspartato Oxidase/genética , Ácido D-Aspártico/metabolismo , Ácido D-Aspártico/farmacologia , DNA Complementar , Perfilação da Expressão Gênica , Biblioteca Gênica , Marcação de Genes , Homozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacologia , Distribuição TecidualRESUMO
The development and the function of central nervous system depend on thyroid hormones. In humans, the lack of thyroid hormones causes cretinism, a syndrome of severe mental deficiency. It is assumed that thyroid hormones affect the normal development and function of the brain by activating or suppressing target gene expression because several genes expressed in the brain have been shown to be under thyroid hormone control. Among these, the Rhes gene, encoding a small GTP-binding protein, is predominantly expressed in the striatal region of the brain. To clarify the role of Rhes in vivo, we disrupted the Rhes gene by homologous recombination in embryonic stem cells and generated mice homozygous for the Rhes null mutation (Rhes(-/-)). Rhes(-/-) mice were viable but weighed less than wild-type mice. Furthermore, they showed behavioral abnormalities, displaying a gender-dependent increase in anxiety levels and a clear motor coordination deficit but no learning or memory impairment. These results suggest that Rhes disruption affects selected behavioral competencies.