Thyroid hormone induces cerebellar neuronal migration and Bergmann glia differentiation through epidermal growth factor/mitogen-activated protein kinase pathway

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.