title: Aberrant cerebellar development of transgenic mice expressing dominant-negative thyroid hormone receptor in cerebellar Purkinje cells.
abstract: To study the role of the thyroid hormone (TH) in cerebellar development, we generated transgenic mice expressing a dominant-negative TH receptor (TR) in cerebellar Purkinje cells. A mutant human TRβ1 (G345R), which binds to the TH-response element but cannot bind to T3, was subcloned into exon 4 of the full-length L7/Pcp-2 gene, which is specifically expressed in Purkinje and retinal rod bipolar cells. The transgene was specifically expressed in Purkinje cells in the postnatal cerebellum. Purkinje cell dendrite arborization was significantly delayed in the transgenic mice. Surprisingly, granule cell migration was also significantly delayed. In the primary cerebellar culture, TH-induced Purkinje cell dendrite arborization was also suppressed. In quantitative real-time RT-PCR analysis, the expression levels of several TH-responsive genes were altered. The expression levels of inositol trisphosphate receptor type 1 and retinoic acid receptor-related orphan receptorα mRNAs, which are mainly expressed in Purkinje cells, and brain-derived neurotrophic factor mRNA, which is expressed in both Purkinje and granule cells, were significantly decreased. The expression levels of neurotrophin-3 and hairless mRNAs, which are mainly expressed in granule cells, and myelin basic protein mRNA, which is mainly expressed in oligodendrocytes, were also decreased. The motor coordination of transgenic mice was significantly disrupted. These results indicate that TH action through its binding to TR in Purkinje cells is required for the normal cerebellar development. TH action through TR in Purkinje cells is also important for the development of other subsets of cerebellar cells such as granule cells and oligodendrocytes.
authors.affiliation: Department of Integrative Physiology (L.Y., T.I., M.X., R.L., N.S., N.K.), Gunma University Graduate School of Medicine, and Department of Laboratory Sciences (Y.X.), Gunma University Graduate School of Health Sciences, Maebashi, Gunma 371-8511, Japan; Department of Neuropsychiatry (M.X.), Keio University School of Medicine, Shinjuku Tokyo 160-8582, Japan; Department of Physiology (R.L.), Universitas Padjadjaran, Bandung 45363, Indonesia; and Harvard Medical School (W.W.C., N.K.), Boston, Massachusetts 02115.
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.forename: Ronny
authors.initials: R
authors.lastname: Lesmana
authors.forename: Yu
authors.initials: Y
authors.lastname: Xiong
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimokawa
authors.forename: William W
authors.initials: WW
authors.lastname: Chin
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Koibuchi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002531:Cerebellum / Q000254:growth & development* / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology*; D011689:Purkinje Cells / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D045442:Rotarod Performance Test
chemical_list: D011988:Receptors, Thyroid Hormone