Thyroid hormone action on brain development is essentially exerted through
regulation of the expression rate of a number of genes some of which have b
een identified in the past 10 years. In the present work we describe the th
yroid hormone regulation of a novel Ras homolog which we have named Rhes (R
as homolog enriched in striatum). The rhes cDNA was previously isolated in
subtractive hybridization experiments aimed at identifying cDNA clones corr
esponding to genes expressed preferentially in the rat striatum. The sequen
ce was found to encode a small GTP-binding protein of the Ras family with h
ighest homology to the dexamethasone-inducible Dexras1. Here we show that r
hes mRNA and protein in the striatum are strongly dependent on the thyroida
l status. Developmentally, Rhes was regulated such that in normal rats ther
e 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 adm
inistration of a single T3 dose to hypothyroid rats normalized rhes mRNA co
ncentration in 8 h, whereas it took 24 h, or more, to normalize the express
ion of rc3, another T3-dependent brain gene, involved in PKC signaling. Dou
ble in situ hybridization using rhes and rc3 riboprobes showed that the bul
k of rhes signal was located in cells expressing rc3. Given the relevance o
f small GTPases in signal transduction it is very likely that control of rh
es, in addition to rc3, is of relevance to explain the actions of thyroid h
ormone in the striatum, a region of the brain especially vulnerable in neur
ological cretinism. (C) 2001 Elsevier Science BY. All rights reserved.