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*Compound via MeSH
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Hazardous Substances DB
*LEVOTHYROXINE
*PROPYL THIOURACIL
Endocrinology Vol. 139, No. 5 2335-2341
Copyright © 1998 by The Endocrine Society

ARTICLES

ROR{alpha} Gene Expression in the Perinatal Rat Cerebellum: Ontogeny and Thyroid Hormone Regulation1

Noriyuki Koibuchi and William W. Chin

Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Dr. Noriyuki Koibuchi, Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Thorn 1004, Boston, Massachusetts 02115. E-mail: koibuchi{at}rascal.med.harvard.edu

Deficiency of thyroid hormone (TH) during the perinatal period results in severe neurological abnormalities in rodent cerebellar development. However, the molecular mechanisms of TH action in the developing cerebellum are not fully understood. Of note, a mutant mouse, staggerer, in which the orphan nuclear hormone receptor ROR{alpha} gene is disrupted, exhibits cerebellar abnormalities similar to those seen in the hypothyroid animals, despite normal thyroid function. We, therefore, speculated that TH (tetraiodo-L-thyronine; T4) may regulate ROR{alpha} gene expression, which then may regulate genes essential for normal brain development. To test this hypothesis, we studied the changes in ROR{alpha} gene expression in perinatal hypothyroid rat cerebellum and the effect of TH replacement using Northern blot analysis, ribonuclease protection assay and in situ hybridization histochemistry. During cerebellar development, an approximately 3-fold increase in the cerebellar content of ROR{alpha} messenger RNA (mRNA) was seen in both propylthiouracil-treated, and propylthiouracil-treated and T4-replaced animals. However, the increase was accelerated when T4 was injected, although the ROR{alpha} mRNA content was identical, with or without T4, by 30 days after birth (P30). In contrast, T4 treatment suppressed the TH receptor {alpha}1 and c-erbA{alpha}2 mRNA content by P30; retinoic acid X receptor-ß mRNA content was not influenced by thyroid status. A significant hybridization signal for ROR{alpha} mRNA was seen only over Purkinje cells in the cerebellar cortex by in situ hybridization histochemistry. These results indicate that TH alters the timing of expression of the ROR{alpha} gene in the Purkinje cells of the cerebellar cortex, which may, in turn, influence Purkinje cell differentiation.




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