Deletion of the thyroid hormone receptor [alpha]1 prevents the structural alterations of the cerebellum induced by hypothyroidism

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, TR[alpha]1 and TR[beta], that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TR[alpha]1 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 TR[alpha]1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TR[beta]-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TR[alpha]1 and TR[beta], prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TR[beta] but not TR[alpha]1, 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 TR[alpha]1 isoform. cerebellar granule cells | Purkinje cells | cretinism | development | GC-1