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

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, TR␣1 and TR␤, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TR␣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␣1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TR␤-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TR␣1 and TR␤, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TR␤ but not TR␣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␣1 isoform.T he physiological actions of thyroid hormone (3,5,3Ј-triiodol-thyronine, T3), including the control of central nervous system (CNS) development, are mediated through interaction with nuclear receptors, which are ligand-modulated transcription factors (1). There are several T3 receptor proteins (TR), which are encoded by two distinct genes, TR␣ and TR␤. The TR␣ gene encodes three proteins, TR␣1, TRv␣2, and TRv␣3 that differ in their carboxyl terminus. From these, only TR␣1 is a bona fide receptor because it binds T3 and activates or represses target genes, whereas the two variants, TRv␣2 and TRv␣3, do not bind T3 and may antagonize T3 action (2-4). In addition to these protein isoforms, there are also truncated protein products of the ␣ gene known as ⌬␣1 and ⌬␣2, which may have a role in intestinal development (5). Several amino terminal protein variants are produced from the TR␤ gene: the two classical receptors, TR␤1 and TR␤2, and two newly identified, T3-binding proteins, TR␤3 and the truncated protein ⌬TR␤3 (6).Although the role of thyroid hormone in health and disease is well known, the physiological roles and specific functions of the T3 receptor isoforms still remain largely unidentified. Mutant mice have been generated that lack the expression of single or multiple products of the TR genes (7-9), and some discrete specific functions could be assigned to individual receptor isoforms. As a consequence of these studies, it is known that TR␤ is involved in the regulation of thyroid stimulating hormone (TSH) secretion, liver metabolism, and hearing (10, 11), whereas ...

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…Indeed, removal of all TRα isoforms rescues the Pax8KO mice from death [69,70]. Deletion of the TRα1 gene also prevents the development of cerebellar abnormalities during TH deprivation [71]. The aporeceptor does not seem to be required for the upregulation of TSH.…”

Thyroid hormone action during brain development: More questions than answers

“…For instance, Bernal and coworkers could show that the cerebellar development in TRalpha1 null mice is not altered even when the animals are rendered hypothyroid (Morte et al, 2002). Moreover, in primary cerebellar cultures, dendritic development of Purkinje cells that do not express TRalpha1 was equally advanced independent of the presence of thyroid hormone whereas Purkinje cells of wildtype animals exhibit only poor dendritic growth if thyroid hormone is not added to the medium (Heuer and Mason, 2003).…”

Thyroid hormone receptor α is a molecular switch of cardiac function between fetal and postnatal life

“…Upon hormone binding, the receptors (holoreceptors) exchange corepressors for coactivators and activate transcription (2). This repressive effect of aporeceptors has been clearly documented in hypothyroid mice for TR␣ in brain, bone, intestine, spleen, and heart (3,4). These observations suggested that the conversion of TR aporeceptors into holoreceptors as a result of a change in T3 concentration in vivo might act as a molecular switch under physiological conditions.…”

“…It is already well known that T3 plays a critical role during this period, regulating the maturation of different organs such as bone, brain, and intestine. All these events are severely impaired in mice devoid of TRs (8)(9)(10)(11)(12) and in hypothyroid mice (3,4). Heart function is critically controlled by T3 in the adult where hypothyroidism and hyperthyroidism respectively induce bradycardia and tachycardia (1).…”