Thyroid hormone and cerebellar development

Abstract

Thyroid hormone (TH) plays a key role in mammalian brain development. The developing brain is sensitive to both TH deficiency and excess. Brain development in the absence of TH results in motor skill deficiencies and reduced intellectual development. These functional abnormalities can be attributed to maldevelopment of specific cell types and regions of the brain including the cerebellum. TH functions at the molecular level by regulating gene transcription. Therefore, understanding how TH regulates cerebellar development requires identification of TH-regulated gene targets and the cells expressing these genes. Additionally, the process of TH-dependent regulation of gene expression is tightly controlled by mechanisms including regulation of TH transport, TH metabolism, toxicologic inhibition of TH signaling, and control of the nuclear TH response apparatus. This review will describe the functional, cellular, and molecular effects of TH deficit in the developing cerebellum and emphasize the most recent findings regarding TH action in this important brain region.

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

“…The stunting of dendritic arborisation in our model was less pronounced than that in studies in TH-deficient rodent and chicken brain (Bouvet et al 1987, Anderson 2008, where TH availability was globally disrupted. Despite reduction in dendritic complexity, the depth of the ML was not noticeably altered in our model (compare Fig.…”

“…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. The role of 3,5,3′-triiodothyronine (T 3 ), the most active TH, in PC dendritogenesis has also been shown in vitro by the addition of T 3 to cerebellar cultures resulting in an increase in PC dendritic branching and calibre in a dose-and time-dependent manner (Heuer & Mason 2003).…”

Thyroid hormone action during brain development: More questions than answers

“…For more in-depth description the reader is referred to excellent reviews published elsewhere (Anderson, 2008;Bernal, 2005;Bernal, 2007;Nunez et al, 2008;St Germain et al, 2009). Moreover, we will not discuss the role of thyroid hormone in retina and cochlea development which has been addressed in a number of interesting papers published elsewhere (Ng et al, 2004;Roberts et al, 2006;Lu et al, 2009;Ng et al, 2009).…”

PBDE flame retardants

“…The importance of TH in brain and somatic development is well established, and small changes in maternal or fetal TH can cause severe motor skill deficiencies and irreversible cognitive impairments. 114 Recent attention has focused on the permissive role of THs in regulating physiological processes in adults, including neurological plasticity, mood, cognition, and reproduction. 90,115 In fish, THs are important mediators of many physiological, developmental, and behavioral processes, including growth and metamorphic transitioning, 116,117 osmoregulation, 118 olfactory imprinting, 119 interrenal regulation, 120 otolith formation, 121 and reproduction, 90,122 often acting in concert with other hormones.…”