Deletion of the thyroid hormone receptor α1 prevents the structural alterations of the cerebellum induced by hypothyroidism

Beatriz Morte, Jimena Manzano, Thomas Scanlan, Björn Vennström, Juan Bernal

Research output: Contribution to journalArticle

183 Scopus citations

Abstract

Thyroid hormone (T3) controls critical aspects of cerebellar development, such as migration of postmitotic granule cells and terminal differentiation of Purkinje cells. T3 acts through nuclear receptors (TR) of two types, TRα1 and TRβ, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRα1 isoform, which normally accounts for about 80% of T3 receptors in the cerebellum. Contrary to what was expected, granule cell migration and Purkinje cell differentiation were normal in the mutant mice. Even more striking was the fact that when neonatal hypothyroidism was induced, no alterations in cerebellar structure were observed in the mutant mice, whereas the wild-type mice showed delayed granule cell migration and arrested Purkinje cell growth. The results support the idea that repression by the TRα1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRβ-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRα1 and TRβ, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRβ but not TRα1, partially corrects Purkinje cell differentiation but has no effect on granule cell migration. Our data indicate that thyroid hormone has a permissive effect on cerebellar granule cell migration through derepression by the TRα1 isoform.

Original languageEnglish (US)
Pages (from-to)3985-3989
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number6
DOIs
StatePublished - Mar 19 2002

Keywords

  • Cerebellar granule cells
  • Cretinism
  • Development
  • GC-1
  • Purkinje cells

ASJC Scopus subject areas

  • General

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