Control of Thyroid Hormone Action in the Developing Rat Brain

Abstract

Thyroid hormones play important roles in brain development. The physiologic function of thyroid hormones in the developing brain is to provide a timing signal that leads to the induction of differentiation and maturation programs during precise stages of development. Inappropriate initiation of these timing events leads to asynchrony in developmental processes and a deleterious outcome. The developing brain is protected from premature thyroid hormone signaling through a variety of measures. Firstly, local brain levels of both thyroxine and triiodothyronine are controlled by ontogenically regulated patterns of production and metabolism. Secondly, developmentally regulated expression of nuclear proteins involved with the nuclear TH response apparatus control the temporal response of brain genes to thyroid hormone. Finally, developmental regulation of TH action modulating transcription factor expression also controls TH action in the developing brain. Together these molecular mechanisms cooperatively act to temporally control TH action during brain development. A description of these controlling mechanisms is the subject of this review.

Developmentally defined regulation of thyroid hormone metabolism by glucocorticoids in the rat

“…For example, dendritic arborization of cerebellar Purkinje cells is only sensitive to thyroid hormones during the first 2 weeks postnatal (Anderson et al 2003), which corresponds to the time-frame during which glucocorticoids stimulate brain thyroid hormone activity. In addition, in the visual cortex, the hypothyroid-induced changes in distribution and number of dendritic spines in pyramidal cells can only be reversed when thyroid hormone replacement is initiated before day 12, whereas a delay beyond postnatal day 12 results in abnormal adult pyramidal cells (Anderson et al 2003).…”

“…We purposely limited the time-frame of our study to 2-4 h post-injection because we were primarily interested in the direct effects of glucocorticoids on thyroid hormone metabolism, and therefore wanted to avoid the possibility that changes in thyroid hormone levels would interfere with the glucocorticoid-induced changes in deiodinase activity. In addition, we decided to focus on day 20 of embryonic development (E20) and postnatal day 12 (P12), because from a developmental point of view these stages roughly delineate the time-frame during which development (especially neural development) is extremely sensitive to thyroid hormones (Bernal 2002, Anderson et al 2003. We also included postnatal day 5 (P5) because this stage corresponds to the human fetus or the chicken embryo just prior to birth or hatching respectively.…”

Thyroid hormone action during brain development: More questions than answers

“…As a consequence, brain development may be influenced by the maternal thyroidal state more in humans than in rodents. For a more detailed time-line describing the ontogenesis of the thyroid hormone system in relation to human and rodent brain development the reader is referred to excellent reviews published elsewhere (Anderson et al, 2003;Bernal, 2007).…”

Identification and characterization of the TRIP8 and REEP3 genes on chromosome 10q21.3 as novel candidate genes for autism

“…33 Our finding therefore implicates a possible role for thyroid hormone signalling in the pathogenesis of the autism seen in the present patient. It is well established that thyroid hormones play a critical role in the regulation of brain development, 34 and therefore, it has been hypothesized that neurobehavioral disabilities of childhood, including autism 35 can be attributed to fetal thyroid endocrine disruption in utero. However, studies investing a possible link between autism and thyroid hormone or T3 receptors remained negative.…”