Thyroid Hormone Role on Cerebellar Development and Maintenance: A Perspective Based on Transgenic Mouse Models

Larissa C Faustino,Tania M Ortiga-Carvalho

doi:10.3389/fendo.2014.00075

Larissa C Faustino, Tania M Ortiga-Carvalho

Open Access

https://doi.org/10.3389/fendo.2014.00075

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Abstract

Cerebellum development is sensitive to thyroid hormone (TH) levels, as THs regulate neuronal migration, differentiation, and myelination. Most effects of THs are mediated by the thyroid hormone receptor (TR) isoforms TRβ1, TRβ2, and TRα1. Studies aimed at identifying TH target genes during cerebellum development have only achieved partial success, as some of these genes do not possess classical TH-responsive elements, and those that do are likely to be temporally and spatially regulated by THs. THs may also affect neurodevelopment by regulating transcription factors that control particular groups of genes. Furthermore, TH action can also be affected by TH transport, which is mediated mainly by monocarboxylate transporter family members. Studies involving transgenic animal models and genome-wide expression analyses have helped to address the unanswered questions regarding the role of TH in cerebellar development. Recently, a growing body of evidence has begun to clarify the molecular, cellular, and functional aspects of THs in the developing cerebellum. This review describes the current findings concerning the effects of THs on cerebellar development and maintenance as well as advances in the genetic animal models used in this field.

Highlights

The thyroid hormones (THs) thyroxine (T4) and 3,5,3 triiodothyronine (T3) are essential for embryonic development and play critical roles in cellular metabolism, acting primarily through the stimulation of oxygen consumption and basal metabolic rate [1, 2]
The cerebellum is located near the rear of the brain stem at the midbrain–hindbrain junction, and this structure is generally thought to coordinate proprioceptive–motor functions, more recently, it has been associated with neurocognition [7, 8]
The majority of TH actions are mediated through the binding of T3 to nuclear thyroid hormone receptors (TRs), which act as ligand-modulated transcription factors that modify the expression of target genes [12]

Summary

INTRODUCTION

The thyroid hormones (THs) thyroxine (T4) and 3,5,3 triiodothyronine (T3) are essential for embryonic development and play critical roles in cellular metabolism, acting primarily through the stimulation of oxygen consumption and basal metabolic rate [1, 2]. Dio2-KO mice display elevated brain T4 levels and reduced T3 content, surprisingly, the observed neurological impairments, which included changes in the cerebellar expression of TH-dependent genes and behavioral defects, were found to be mild compared with those observed in hypothyroidism [42, 76]. These data suggest that decreased local T3 production can be largely compensated for by increased T3 uptake from circulation, and this was later confirmed by experiments carried out in double Dio1/Dio2-KO mice, which demonstrated normal serum T3 concentrations and only mild neurological phenotypes [21]. TR-β expression is confined to a Frontiers in Endocrinology | Thyroid Endocrinology

Thyroid gland knockout dysgenesis

Normal Purkinje cell morphology

Reduced locomotor activity

Findings

Delayed Purkinje cells development and maturation