The Influence of Thyroid Hormone on Ca²⁺ Signaling Pathways During Embryonal Development

Thyroid hormones influence brain development through the regulation of gene expression. Ca²⁺-dependent gene expression is a major pathway controlled by the Ca²⁺/calmodulin-dependent protein kinase IV (CaMKIV), which in turn is induced by the thyroid hormone T₃, as also demonstrated in a mouse embryonic stem cell line. In addition, T₃ controls the expression of neurexin, synaptotagmin2 (SYT2), synaptotagmin-related gene1 (SRG1), and a number of other genes involved in neurotransmitter release in a Ca²⁺-dependent manner. It has been noticed that the development of dopaminergic neurons by evoking significant calcium entry occurs through TRPC calcium channels. It was also demonstrated that the T₃-mediated development of an early neuronal network is characteristic for depolarizing GABAergic neurons concomitant with intracellular calcium transients. An important aspect of T₃-dependent regulation of gene expression in the developing brain is its modulation by the transcription activator COUP-TF1. Regulation of alternative splicing by CaMKIV is another important aspect for embryonal neural development since it can lead to the expression of PMCA1a, the neuronal-specific isoform of the plasma membrane calcium pump. Maternal hypothyroidism or CaMKIV deficiency can have a severe influence on fetal brain development.