Liao Wen-Lin, Liu Fu-Chin
Institute of Neuroscience, National Yang-Ming University, 155 Li-Rum Street, Taipei 11211, Taiwan.
Eur J Neurosci. 2005 Jun;21(12):3262-8. doi: 10.1111/j.1460-9568.2005.04178.x.
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, RARbeta and RXRgamma 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 RARbeta and RXRgamma may mediate DARPP-32 induction by retinoids. To test this hypothesis, we used the gain-of-function approach to ectopically express RARbeta and RXRgamma in the developing cerebral cortex that lacked these two retinoid receptors. Ectopic expression of RARbeta1, but not RXRgamma1, up-regulated DARPP-32 in the cortical explant culture. Notably, DARPP-32 was up-regulated only by the RARbeta1 isoform, but not by other RARbeta isoforms. Our study suggests that RARbeta signaling may regulate DARPP-32 gene expression by an isoform-specific mechanism in developing telencephalic neurons. The molecular diversity of RARbeta isoforms may underlie parts of the complex gene regulation by retinoids during neural development.
多巴胺和3':5'-环磷酸腺苷调节的磷蛋白（DARPP-32）是多巴胺神经传递的关键分子。发育中的大脑中DARPP-32调节的分子机制仍不清楚。先前的研究表明，视黄酸能够在纹状体细胞培养中诱导DARPP-32，这表明视黄酸是控制DARPP-32表达的候选分子。在本研究中，我们首先通过逆转录聚合酶链反应（RT-PCR）研究了发育中的大鼠端脑中视黄酸受体及其相关辅因子的表达谱。结果显示，在视黄酸受体中，RARβ和RXRγ几乎选择性地在发育中的纹状体中表达。相比之下，视黄酸受体相关的转录辅因子，包括N-CoR和SMRT的共抑制因子以及SRC-1和P/CAF的共激活因子，在发育中的端脑中普遍表达。鉴于先前的研究发现DARPP-32在纹状体培养中可被视黄酸诱导，但在皮质培养中则不然，我们推测纹状体选择性的RARβ和RXRγ可能介导视黄酸对DARPP-32的诱导。为了验证这一假设，我们采用功能获得法在缺乏这两种视黄酸受体的发育中的大脑皮质中异位表达RARβ和RXRγ。RARβ1而非RXRγ1的异位表达上调了皮质外植体培养物中的DARPP-32。值得注意的是，只有RARβ1亚型上调了DARPP-32，而其他RARβ亚型则没有。我们的研究表明，RARβ信号可能通过一种亚型特异性机制在发育中的端脑神经元中调节DARPP-32基因表达。RARβ亚型的分子多样性可能是视黄酸在神经发育过程中复杂基因调控的部分基础。
