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

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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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (grant number 30800896, 81102126) and the Program for Liaoning Excellent Talents in University (grant number LJQ2012070).

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Department of Occupational and Environmental Health, School of Public Health, China Medical University, 92 North 2nd Road, Shenyang, 110001, People’s Republic of China

    Yuan Wang, Yi Wang, Jing Dong, Wei Wei, Binbin Song, Hui Min, Ye Yu, Xibing Lei, Ming Zhao & Jie Chen

  2. Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

    Weiping Teng

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  1. Yuan Wang
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  2. Yi Wang
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Wang, Y., Wang, Y., Dong, J. et al. Developmental Hypothyroxinemia and Hypothyroidism Reduce Proliferation of Cerebellar Granule Neuron Precursors in Rat Offspring by Downregulation of the Sonic Hedgehog Signaling Pathway. Mol Neurobiol 49, 1143–1152 (2014). https://doi.org/10.1007/s12035-013-8587-3

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