R.M. and C.E. contributed equally to this work.
Thyroid hormone induces cerebellar neuronal migration and Bergmann glia differentiation through epidermal growth factor/mitogen-activated protein kinase pathway
Article first published online: 11 NOV 2010
© 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Volume 33, Issue 1, pages 26–35, January 2011
How to Cite
Martinez, R., Eller, C., Viana, N. B. and Gomes, F. C. A. (2011), Thyroid hormone induces cerebellar neuronal migration and Bergmann glia differentiation through epidermal growth factor/mitogen-activated protein kinase pathway. European Journal of Neuroscience, 33: 26–35. doi: 10.1111/j.1460-9568.2010.07490.x
- Issue published online: 4 JAN 2011
- Article first published online: 11 NOV 2010
- Received 5 May 2010, revised 29 September 2010, accepted 1 October 2010
- 3-3′-5 tri-iodo-L-thyronine;
- epidermal growth factor;
- mitogen-activated protein kinase;
- neuronal migration
Cerebellar development in the postnatal period is mainly characterized by an intense cellular proliferation in the external granular layer, followed by migration of granular cells in the molecular layer along the Bergmann glia (BG) fibers. Cerebellar ontogenesis undergoes dramatic modulation by thyroid hormones (THs), although their mechanism of action in this organ is still largely unknown. We previously demonstrated that THs induce astrocytes to secrete epidermal growth factor (EGF), which thus promotes cerebellar neuronal proliferation and extracellular matrix remodeling in vitro. In the present study, we investigated the effect of the TH/EGF pathway on granule neuronal migration. By taking advantage of rat explant and dissociated culture assays, we showed that cerebellar astrocytes treated with TH promote granule cell migration. The addition of neutralizing antibodies against EGF or the pharmacological inhibitor of EGF signaling, bis-tyrphostin, completely inhibited TH-astrocyte-induced migration. Likewise, the addition of EGF itself greatly increased neuronal migration. Treatment of BG-dissociated cultures by EGF dramatically induced an alteration in cell morphology, characterized by an elongation in the glial process. Both neuronal migration and BG elongation were inhibited by the mitogen-activated protein kinase pathway inhibitor PD98059, suggesting that these events might be associated. Together, our results suggest that, by inducing EGF secretion, THs promote neuronal migration through BG elongation. Our data provide new clues to the molecular mechanism of THs in cerebellar development, and may contribute to a better understanding of some neuroendocrine disorders associated with migration deficits.