Developmental Hypothyroxinemia and Hypothyroidism Reduce Proliferation of Cerebellar Granule Neuron Precursors in Rat Offspring by Downregulation of the Sonic Hedgehog Signaling Pathway

Abstract

Iodine deficiency (ID)-induced hypothyroxinemia and hypothyroidism during development result in dysfunction of the central nervous system, affecting psychomotor and motor function, although the underlying mechanisms causing these alterations are still unclear. Therefore, our aim is to study the effects of developmental hypothyroxinemia, caused by mild ID, and developmental hypothyroidism, caused by severe ID or methimazole (MMZ), on the proliferation of cerebellar granule neuron precursors (CGNPs), an excellent experimental model of cerebellar development and function. The sonic hedgehog (Shh) signaling pathway is essential for CGNP proliferation, and as such, its activation is also investigated here. A maternal hypothyroxinemia model was established in Wistar rats by administrating a mild ID diet, and two maternal hypothyroidism models were developed either by administrating a severe ID diet or MMZ water. Our results showed that hypothyroxinemia and hypothyroidism reduced proliferation of CGNPs on postnatal day (PN) 7, PN14, and PN21. Accordingly, the mean intensity of proliferating cell nuclear antigen and Ki67 nuclear antigen immunofluorescence was reduced in the mild ID, severe ID, and MMZ groups. Moreover, maternal hypothyroxinemia and hypothyroidism reduced expression of the Shh signaling pathway on PN7, PN14, and PN21. Our study supports the hypothesis that developmental hypothyroxinemia induced by mild ID, and hypothyroidism induced by severe ID or MMZ, reduce the proliferation of CGNPs, which may be ascribed to the downregulation of the Shh signaling pathway.

Influence of maternal thyroid hormones during gestation on fetal brain development

“…Several genes involved in cell cycle regulation and cell proliferation are found to be regulated by TH in the developing brain (Dowling et al, 2000, Bansal et al, 2005, Morte et al, 2010, Qiu et al, 2010, Wang et al, 2014). In addition, neural progenitors in the VZ of rats express TRα1, Mct8 transporters and deiodinase II, and maternal thyroid hormone deficiency leads to a delay in symmetrical divisions of these progenitors, as well as a reduced cell cycle length and a corresponding reduction of the progenitor pool (Mohan et al, 2012).…”

Maternal Hypothyroxinemia-Induced Neurodevelopmental Impairments in the Progeny

“…In order to clarify the underlying mechanisms of how maternal hypothyroxinemia affects the cerebellum development and function, an animal model was established by administering a mildly iodine-deficient diet to dams [102]. Subsequent results suggested a reduction in the proliferation of cerebellar granule neuron precursors in hypothyroxinemia offspring, which may be related to the downregulation of the sonic hedgehog signaling pathway.…”

An Evo-Devo Approach to Thyroid Hormones in Cerebral and Cerebellar Cortical Development: Etiological Implications for Autism

“…Other T3-regulated genes such as CNN1 (calporin), which is an actin associated protein, also exerts a control of cell cycle during neurogenesis (197). Recently, it has been found that developmental mild and severe hypothyroxinemia and MMI-induced hypothyroidism alters Shh signaling pathway in the cerebellar granule cell precursors, resulting in downregulation of D1 and D2 cyclins, of E2F1 expression, and in reduced cell proliferation (198). However, it still remains unclear to what extent thyroid hormones affect symmetrical and asymmetrical divisions of neocortical progenitor cells.…”