Impaired extrapyramidal function caused by the targeted disruption of retinoid X receptor RXRgamma1 isoform.
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.
Saga
Y
Y
Banyu Tsukuba Research Institute (Merck) Tsukuba, Ibaraki, 300-33 Japan.
Kobayashi
M
M
Ohta
H
H
Murai
N
N
Nakai
N
N
Oshima
M
M
Taketo
M M
MM
D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000201:enzymology; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D005116:Extrapyramidal Tracts / Q000502:physiology*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism*; D047488:Retinoid X Receptors; D013194:Staining and Labeling; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
D018492:Dopamine Antagonists; D020033:Protein Isoforms; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002795:Choline O-Acetyltransferase; D001616:beta-Galactosidase; D004298:Dopamine