The human RC3 gene homolog, NRGN contains a thyroid hormone-responsive element located in the first intron

NRGN is the human homolog of the neuron-specific rat RC3/neurogranin gene. This gene encodes a postsynaptic 78-amino acid protein kinase substrate tha t binds calmodulin in the absence of calcium, and that has been implicated in dendritic spine formation and synaptic plasticity. In the rat brain RC3 is under thyroid hormone control in specific neuronal subsets in both devel oping and adult animals. To evaluate whether the human gene is also a targe t of thyroid hormone we have searched for T-3-responsive elements in NRGN c loned genomic fragments spanning the whole gene. Labeled DNA fragments were incubated with T-3 receptors (T3R) and 9-cis-retinoic acid receptors and i mmunoprecipitated using an anti T3R antibody. A receptor-binding site was l ocalized in the first intron, 3000 bp downstream from the origin of transcr iption. Footprinting analysis revealed the sequence GGATTAAATGAGGTAA, close ly related to the consensus T-3-responsive element of the direct repeat (DR 4) type. This sequence binds the T3R-9-cis-retinoic acid receptors heterodi mers, but not T3R monomers or homodimers, and is able to confer regulation by T3R and T-3 when fused upstream of the NRGN or thymidine kinase promoter s. The data reported in this work suggest that NRGN is a direct target of t hyroid hormone in human brain, and that control of expression of this gene could underlay many of the consequences of hypothyroidism on mental states during development as well as in adult subjects.