The Role of Thyroid Hormone on Cerebellar Development

Abstract

Thyroid hormone plays a crucial role in cerebellar development. Deficiency of thyroid hormone results in abnormal cerebellar growth and differentiation. In rodent, thyroid hormone mainly affects cerebellar development during the first 2 weeks of postnatal life. Thyroid hormone replacement after such critical period cannot fully rescue abnormal cerebellar development induced by perinatal hypothyroidism. Thyroid hormone receptor (TR) is a ligand-regulated transcription factor that binds to a specific DNA sequence called thyroid-hormone-responsive element. TR recruits various coregulators such as coactivator and corepressor in a ligand-dependent manner to regulate transcription of target genes. In cerebellum, at least three different TRs are expressed in a cell-specific manner. TRbeta1 is expressed predominantly in the Purkinje cell, whereas TRalpha1 in other subset of neurons. Although these TRs are widely expressed during the cerebellar development and their levels are greater in adult, the expression of many thyroid-hormone-responsive genes is altered by thyroid hormone status only during early postnatal critical period. Not only the expression levels of TRs but also those of cofactors and other nuclear receptors may play a role in regulating thyroid hormone sensitivity in the developing cerebellum. In this article, the effect of thyroid hormone on morphological development of cerebellum and molecular mechanisms of thyroid hormone action are introduced. Furthermore, possible involvement of other nuclear receptors and cofactors in thyroid hormone action in the developing cerebellum is also discussed.