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Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRgamma1 isoform
1Banyu Tsukuba Research Institute (Merck) Tsukuba, Ibaraki, 300-33 Japan.
Background:
Retinoid X receptors RXRalpha, beta and gamma exert multiple functions in the genetic regulation of mammalian signalling systems by forming heterodimeric complexes with several nuclear ligand receptors. In contrast to the widespread expression of RXRalpha and RXRbeta, the expression of RXRgamma is restricted to particular tissues in which RXRgamma1 is the major isoform expressed in the mouse corpus striatum.
Results:
To investigate the function of this particular isoform RXRgamma1, we generated RXRgamma1 gene-knockout mice by homologous recombination in ES cells. Both heterozygous and homozygous mice showed severe runting after birth, which often resulted in the early death of mice of the 129/C57BL-6 genetic background. Independent of genetic background, however, the expression of choline acetyltransferase (ChAT) in the cholinergic interneurones in the striatum (caudal putamen) was markedly reduced in the RXRgamma1 gene-null mice. Furthermore, the mutant exhibited an altered response to the administration of dopamine receptor antagonists, haloperidol and chlorpromazine, which normally induce catalepsy in mice.
Conclusions:
These results strongly suggest that RXRgamma1 plays an important role in either the development or activation of cholinergic neurones in nigrostriatal extrapyramidal pathways.
Insights
Mice lacking the Retinoid X receptor gamma 1 (RXRgamma1) isoform showed developmental issues and reduced choline acetyltransferase in the striatum. This suggests RXRgamma1 is crucial for cholinergic neuron function in the nigrostriatal pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Retinoid X receptors (RXRs) are crucial for gene regulation, forming heterodimers with nuclear receptors.
- While RXRalpha and RXRbeta are widely expressed, RXRgamma expression is tissue-restricted.
- RXRgamma1 is the predominant isoform in the mouse corpus striatum.
Purpose of the Study:
- To investigate the specific function of the RXRgamma1 isoform.
- To determine the role of RXRgamma1 in the development and function of the central nervous system.
Main Methods:
- Generation of RXRgamma1 gene-knockout mice using homologous recombination in embryonic stem (ES) cells.
- Analysis of mouse phenotype, including growth and survival rates.
- Assessment of choline acetyltransferase (ChAT) expression in striatal cholinergic interneurons.
- Evaluation of behavioral responses to dopamine receptor antagonists.
Main Results:
- RXRgamma1 knockout mice exhibited severe runting and early mortality, irrespective of genetic background.
- A significant reduction in choline acetyltransferase (ChAT) expression was observed in the striatum of RXRgamma1-null mice.
- Mutant mice displayed altered responses to haloperidol and chlorpromazine, dopamine receptor antagonists.
Conclusions:
- RXRgamma1 plays a critical role in the development or activation of cholinergic neurons within the nigrostriatal extrapyramidal pathways.
- These findings highlight the specific importance of the RXRgamma1 isoform in motor control and neuronal function.