Thyroid hormone regulates the expression of NeuroD/BHF1 during the development of rat cerebellum

During the postnatal development of the rat cerebellum, there is an extensive proliferation of granular neurones in the external layer, followed by their migration and differentiation in the internal layer. These processes are impaired by neonatal hypothyroidism and can be restored by thyroid hormone therapy. They are also abolished in transgenic mice in which the neuroD gene is not expressed. This gene encodes a basic helix-loop-helix (bHLH) transcription factor (NeuroD), which induces the differentiation of neuronal precursors. We studied the expression of neuroD/BHF1-A mRNA during the postnatal development of euthyroid and hypothyroid rats, and compared it with that of neurotrophin-3 (NT-3), a marker of granular neurone differentiation. In euthyroid animals, the neuroD/BHF1-A mRNA increases 6-fold between days 4 and 15 after birth, and then decreases to 50% of this level in the adult. NT-3 mRNA expression followed a similar pattern, although it was increased only 3-fold. Hypothyroidism reduced both mRNA levels by 35-45%, depending on the postnatal stage. In hypothyroid pups, the injection of triiodothyronine (T3) restored normal levels of both mRNAs within 6 h. In 15-day old hypothyroid rats, the amount of NeuroD protein was reduced by about 35%. It increased about 2-fold 24 h after T3 injection. In conclusion, our results indicate that thyroid hormones (TH) regulate the expression of NeuroD during the "critical period" of cerebellum development. This regulation may constitute an early event in the control of differentiation of the cerebellar granular neurones by TH.