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

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.

Maternal hormonal milieu influence on fetal brain development

“…Several thyroid hormone membrane transporters have been described; however, the most relevant are monocarboxylate transporter 8 (Mct8), with affinity for both T3 and T4, and organic anion transporter 1C1 (OATP1C1), which has much higher selectivity for T4 (Landers & Richard, 2017;Figure 2). In fact, developing human brain is relatively impermeable to T3, with about 80% of T3 in the cerebral cortex being produced by local deiodination of free T4 (Faustino & Ortiga-Carvalho, 2014;Guadaño-Ferraz, Obregón, St Germain, & Bernal, 1997; Figure 2). Briefly, after being taken up by astrocytes, T4 is deionized to T3 by deiodinase type 2 and, posteriorly, T3 is exported through MCT8 transporter (Guadaño-Ferraz et al, 1997;Roti, Fang, Green, Emerson, & Braverman, 1981).…”

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

“…Distinct cerebellar cell types depend on adequate TH levels as well as a correct timing of TH access to coordinate key cellular events driving the development and functional maintenance of the cerebellum (Koibuchi 2008, Faustino & Ortiga-Carvalho 2014. As such, induction of hypothyroidism in animal models such as rat and chicken 232:2 results in a number of morphological alterations, including impaired Purkinje cell (PC) dendritic arborisation, delayed granule cell (GC) migration from the external germinal layer (EGL) towards their final cortical position in the internal granular layer (IGL), delayed myelination and changes in synaptogenesis between cerebellar neurons and afferent neuronal fibres (Bouvet et al 1987, Verhoelst et al 2004, Anderson 2008, Shimokawa et al 2014.…”

Effect of Thyroid Hormones on Neurons and Neurodevelopment

“…In the embryonic chicken brain, the presence of D3 and L/type amino acid transporter 1 (LAT1) on brain capillary surface controls the main doorway of T3 to CNS [25]. Notably, T3 levels and T3/T4 ratio are higher in the brain than in the systemic circulation as previously reported in mammalian brain studies [26]. D2 has also been found in tanycytes, interneurons, and astrocytes [27]; the latter are able to provide T3 to neurons by fT4 conversion.…”

“…D2 has also been found in tanycytes, interneurons, and astrocytes [27]; the latter are able to provide T3 to neurons by fT4 conversion. A second regulatory level is localized in the choroid plexus, where a system of transporters and receptors (OATP1C1, LAT1, LAT2, MCT8, and MCT10) needs to be better elucidated [26]. When some of these are lacking, in mice cerebellar development delay, impaired myelination, and poor locomotor outcomes are developed [28], while even worse neurological symptoms are present in humans (Allan-Herndon-Dudley syndrome).…”

“…When some of these are lacking, in mice cerebellar development delay, impaired myelination, and poor locomotor outcomes are developed [28], while even worse neurological symptoms are present in humans (Allan-Herndon-Dudley syndrome). Such differences in human and mouse TH brain uptakes may be explained by the synergic cooperation of other transporters [26]. …”