Thyroid hormone action on brain development is essentially exerted through regulation of the expression rate of a number of genes some of which have been identified in the past 10 years. In the present work we describe the thyroid hormone regulation of a novel Ras homolog which we have named Rhes (Ras homolog enriched in striatum). The rhes cDNA was previously isolated in subtractive hybridization experiments aimed at identifying cDNA clones corresponding to genes expressed preferentially in the rat striatum. The sequence was found to encode a small GTP-binding protein of the Ras family with highest homology to the dexamethasone-inducible Dexras1. Here we show that rhes mRNA and protein in the striatum are strongly dependent on the thyroidal status. Developmentally, Rhes was regulated such that in normal rats there was an increased rhes mRNA content in the striatum after postnatal day 5 (P5). Rhes concentration in hypothyroid rats was similar to that of normal rats at P5, but the subsequent age-dependent increase was blunted. The administration of a single T3 dose to hypothyroid rats normalized rhes mRNA concentration in 8 h, whereas it took 24 h, or more, to normalize the expression of rc3, another T3-dependent brain gene, involved in PKC signaling. Double in situ hybridization using rhes and rc3 riboprobes showed that the bulk of rhes signal was located in cells expressing rc3. Given the relevance of small GTPases in signal transduction it is very likely that control of rhes, in addition to rc3, is of relevance to explain the actions of thyroid hormone in the striatum, a region of the brain especially vulnerable in neurological cretinism.