Neuronal expression of synaptotagmin-related gene 1 is regulated by thyroid hormone during cerebellar development

Thyroid hormone (TH) is essential for proper brain development, acting thro ugh nuclear receptors that modulate the expression of specific genes in res ponse to hormone binding. In a screen for genes regulated by TH in the rat cerebellum, we recently identified a novel gene, synaptotagmin-related gene 1 (Srg1). The Srg1 protein is structurally similar to synaptotagmins, a fa mily of proteins involved in regulating neurotransmission. To elucidate a p otential role of Srg1 in brain development, we have investigated the develo pmental and TH-regulated expression of Srg1 in the neonatal rat brain. We s how that expression of both Srg1 RNA and protein is detected only in the br ain and specifically in neurons. Srg1 mRNA and protein levels increase post natally, nearing adult levels after the third postnatal week. Neonatal TH d eficiency results in a significant reduction and delay in expression of bot h Srg1 RNA and protein. Using immunohistochemistry, we were able to detect Srg1 protein in numerous brain regions. In the cerebellum, Srg1 protein is localized to the molecular layer, indicating that it is highly expressed in granule cell axons. To further examine Srg1 expression in cerebellar granu le cells (CGCs), we used an in vitro cell culture model. In primary culture s of CGCs, Srg1 expression is significantly reduced in the absence of TH. S rg1 mRNA is rapidly upregulated in cultured CGCs, suggesting a direct respo nse to TH. Neuronal and TH-regulated expression of Srg1, together with its localization to neurites, implicates Srg1 as an important component of the program of gene expression induced by TH in the developing brain.