Endocrinol Metab.  2021 Aug;36(4):703-716. 10.3803/EnM.2021.1150.

The Role of Thyroid Hormone in the Regulation of Cerebellar Development

• Ishii S
• Amano I
• Koibuchi N

• KMID: 2519658
• DOI: http://doi.org/10.3803/EnM.2021.1150

Abstract

The proper organized expression of specific genes in time and space is responsible for the organogenesis of the central nervous system including the cerebellum. The epigenetic regulation of gene expression is tightly regulated by an intrinsic intracellular genetic program, local stimuli such as synaptic inputs and trophic factors, and peripheral stimuli from outside of the brain including hormones. Some hormone receptors are expressed in the cerebellum. Thyroid hormones (THs), among numerous circulating hormones, are well-known major regulators of cerebellar development. In both rodents and human, hypothyroidism during the postnatal developmental period results in abnormal morphogenesis or altered function. THs bind to the thyroid hormone receptors (TRs) in the nuclei and with the help of transcriptional cofactors regulate the transcription of target genes. Gene regulation by TR induces cell proliferation, migration, and differentiation, which are necessary for brain development and plasticity. Thus, the lack of TH action mediators may directly cause aberrant cerebellar development. Various kinds of animal models have been established in a bid to study the mechanism of TH action in the cerebellum. Interestingly, the phenotypes differ greatly depending on the models. Herein we summarize the actions of TH and TR particularly in the developing cerebellum.

Keyword

Cerebellum; Gene expression regulation; developmental; Receptors; cytoplasmic and nuclear; Organogenesis; Thyroid hormones

Figure

• 

  Fig. 1 Schematic diagram of multiple factors involved in brain development and plasticity.

• 

  Fig. 2 Thyroid hormone receptors and their related proteins generated from THRA or THRB gene. Numerals indicate the number of amino acids. TR, thyroid hormone receptor.

• 

  Fig. 3 Schematic figure showing the mechanisms of thyroid hormone receptor (TR)-mediated transcription. RXR, retinoid X receptor; TRE, thyroid hormone response element; TF, transcriptional factor.

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