Deletion of the thyroid hormone receptor α1 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, 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.

甲状腺激素（T3）调控小脑发育的关键进程，例如有丝分裂后颗粒细胞的迁移以及浦肯野细胞（Purkinje cells）的终末分化。T3通过两类核受体（TR）发挥作用，即TRα1与TRβ，二者可分别抑制或激活基因表达。我们对缺失TRα1亚型的发育中小鼠的小脑结构进行了分析——TRα1通常占小脑内T3受体总量的约80%。与预期相悖的是，突变小鼠的颗粒细胞迁移与浦肯野细胞分化均未出现异常。更值得关注的是，当诱导产生新生儿甲状腺功能减退症时，突变小鼠的小脑结构未观察到任何改变，而野生型小鼠则出现了颗粒细胞迁移延迟以及浦肯野细胞生长停滞的情况。上述结果支持了这一观点：由TRα1空载受体介导的阻遏作用，而非甲状腺激素的缺乏，是导致甲状腺功能减退表型的原因。这一结论得到了TRβ选择性化合物GC-1相关实验的佐证。向甲状腺功能减退的动物施用可结合TRα1与TRβ的T3，能够阻止小脑结构出现任何缺陷。与之相反，施用仅结合TRβ而不结合TRα1的GC-1，仅能部分修复浦肯野细胞的分化缺陷，对颗粒细胞迁移则无任何改善作用。我们的研究数据表明，甲状腺激素通过TRα1亚型的去阻遏作用，对小脑颗粒细胞迁移发挥允许效应。