Comparative approaches to understanding thyroid hormone regulation of neurogenesis

(A) Timing of embryonic brain development for two non-mammalian species (Xenopus, chicken) and mouse. Before the onset of fetal TH production (see purple arrow), maternal THs regulate the early stages of fetal cortical neurogenesis (proliferation, migration and differentiation of neuronal progenitors). In both Xenopus and chicken, maternal THs are stored in the yolk. In mammals, maternal THs pass through the placenta. Alteration in TH levels (e.g. iodine accessibility, certain EDCs) alter neurological processes in the offspring, leading to cognitive deficits.(B) Localization of adult neurogenic niches in vertebrates. Compared to anamniotes (Xenopus) where adult neurogenesis occurs in most brain regions, neural stem cell (NSC) proliferation is limited to the forebrain in amniotes (birds and mammals). In mammals, adult neurogenesis is found in two main niches, the SGZ of the hippocampus and the SVZ lining the lateral ventricles. The impact of EDCs on adult neurogenesis is not well known.(C) TH regulation of both SVZ and hippocampal adult neurogenesis in mammals. In the adult SVZ (left panel), NSCs divide asymmetrically to give rise to highly proliferative progenitors. Under normal homeostatic conditions, they give rise mainly to neuroblasts that migrate toward the olfactory bulb where they differentiate into interneurons. T3 regulates both proliferation and cell fate decision within the adult SVZ. T3/TRα1 act as a neurogenic switch by repressing Sox2 in progenitors, determining a neuronal phenotype. In the hippocampal SGZ niche (right panel), NSCs divide asymmetrically to generate transitory progenitors (2a progenitors) capable to produce migrating neuroblasts (2b progenitors) and then immature and mature granule neurons. Type 2b and 3 progenitors respond to TH signalling. In presence of T3, TRα1 increases proneural gene expression. Hypothyroidism or TRα1 aporeceptor overexpression decreases neurogenesis (proneural gene expression is reduced leading to a decrease of cell survival).247