Developmental hypothyroxinemia and hypothyroidism reduce proliferation of cerebellar granule neuron precursors in rat offspring by downregulation of the sonic hedgehog signaling pathway

Mol Neurobiol. 2014 Jun;49(3):1143-52. doi: 10.1007/s12035-013-8587-3. Epub 2013 Nov 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / physiology*
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / metabolism*
  • Down-Regulation / physiology
  • Female
  • Hedgehog Proteins / biosynthesis*
  • Hypothyroidism / blood*
  • Hypothyroidism / pathology
  • Male
  • Neural Stem Cells / physiology*
  • Rats
  • Rats, Wistar
  • Signal Transduction / physiology
  • Thyroxine / blood*


  • Hedgehog Proteins
  • Shh protein, rat
  • Thyroxine