Nongenomic actions of thyroid hormone during fetal brain development

Abstract

Purpose of review Thyroid hormone has long been identified as an essential regulatory factor in the brain developmental program. Although transcriptional regulation is the traditional mechanism of thyroid hormone action, and multiple genes have been identified that are altered in response to thyroid hormone, the demonstration of developmentally important T3-regulated genes has been elusive. In fact, the lack of abnormal brain development in mice lacking all known thyroid hormone receptors suggests a role for actions independent of thyroid hormone-thyroid hormone receptor binding. This review examines the role of nongenomic actions of thyroid hormone on brain development. Recent findings A possible role for unliganded thyroid hormone receptors in brain development has been proposed as a result of the absence of a significant abnormal phenotype in thyroid hormone receptor knockout mice. Also, actions of thyroid hormone on the organization of the actin cytoskeleton, leading to thyroid hormone-dependent regulation of neuronal migration, neuronal process formation, and deposition of the neuronal guidance molecule laminin on the astrocyte surface, has recently been reported. These two topics are discussed in detail. Summary Although regulated gene expression, either due to thyroid hormone-thyroid hormone receptor binding or via the unliganded thyroid hormone receptor, plays a role in thyroid hormone-dependent brain development, it is clear that other nongenomic actions also participate in the brain developmental program. The regulation of cytoskeletal organization leading to altered interactions between astrocytes, laminin, and neurons during development likely plays a major role in neuronal migration, neuronal process outgrowth, and the establishment of the complex wiring system of the brain.