Alteration of cerebellar neurotropin messenger ribonucleic acids and the lack of thyroid hormone receptor augmentation by staggerer-type retinoic acid receptor-related orphan receptor-alpha mutation

Chun Hong Qiu, Noriaki Shimokawa, Toshiharu Iwasaki, Ishwar Parhar, Noriyuki Koibuchi

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    The mutant mouse staggerer ( sg) harbors a deletion within the gene encoding the retinoic acid receptor-related orphan receptor-alpha ( ROR alpha). Homozygotes show aberrant cerebellar development. However, the mechanisms responsible for the cerebellar defect are still poorly understood. In the present study, the involvement of neurotropins ( NTs), including nerve growth factor, brain-derived neurotropic factor, NT-3 and NT-4/5, and their receptors, which play a crucial role in brain development, on the cerebellar defects of sg mice was studied by semiquantitative RT-PCR and in situ hybridization histochemistry. An evident alteration of these mRNA levels was observed in both heterozygotes and homozygotes. Such difference was most evident in the internal granule cell layer. Because the changes in NT expression as well as morphological alterations in sg cerebellum are similar to those in hypothyroid animals, the effect of mutant ROR alpha( RORsg) on transcriptional regulation through the thyroid hormone ( TH) response element or the ROR response element ( RORE) was then studied. RORsg neither activated the transcription through RORE nor suppressed ROR alpha-induced transcription, indicating that it does not function as a dominant negative inhibitor. On the other hand, although wild-type ROR alpha augmented TH receptor ( TR) alpha 1/beta 1-mediated transcription through various TH response elements, RORsg was not effective in augmenting TR action. These results suggest that the cerebellar defect of the sg mouse is partly caused by the altered expression of NTs and the lack of augmentation of TR-mediated transcription by ROR alpha as well as the absence of ROR alpha action through RORE.
    Original languageEnglish
    Pages (from-to)1745 - 1753
    Number of pages9
    Issue number4
    Publication statusPublished - 2007

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