RARβ isoform‐specific regulation of DARPP‐32 gene expression: an ectopic expression study in the developing rat telencephalon

Dopamine and adenosine 3′:5′‐monophosphate‐regulated phosphoprotein (DARPP‐32) is a key molecule for dopamine neurotransmission. The molecular mechanisms underlying the regulation of DARPP‐32 in the developing brain remains elusive. Previous studies have shown that retinoids are capable of inducing DARPP‐32 in striatal cell culture, suggesting that retinoids are candidate molecules for controlling DARPP‐32 expression. In the present study, we first studied the expression profiles of retinoid receptors and their associated co‐factors in the developing rat telencephalon by RT‐PCR. The results showed that among the retinoid receptors, RARβ and RXRγ were nearly selectively expressed in the developing striatum. By contrast, the retinoid receptors associated transcriptional co‐factors, including the co‐repressors of N‐CoR and SMRT, and the co‐activators of SRC‐1 and P/CAF, were ubiquitously expressed in the developing telencephalon. In light of the previous findings that DARPP‐32 was inducible by retinoids in striatal culture, but not in cortical culture, we hypothesized that the striatum‐selective RARβ and RXRγ may mediate DARPP‐32 induction by retinoids. To test this hypothesis, we used the gain‐of‐function approach to ectopically express RARβ and RXRγ in the developing cerebral cortex that lacked these two retinoid receptors. Ectopic expression of RARβ1, but not RXRγ1, up‐regulated DARPP‐32 in the cortical explant culture. Notably, DARPP‐32 was up‐regulated only by the RARβ1 isoform, but not by other RARβ isoforms. Our study suggests that RARβ signaling may regulate DARPP‐32 gene expression by an isoform‐specific mechanism in developing telencephalic neurons. The molecular diversity of RARβ isoforms may underlie parts of the complex gene regulation by retinoids during neural development.