Regulation of gene expression and compartment formation by retinoid receptors in the developing striatum

• Main Authors: Wen-Lin Liao, 廖文霖
• Other Authors: Fu-Chin Liu
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/71290815858707055031

博士 === 國立陽明大學 === 神經科學研究所 === 93 === Retinoic acid (RA) is a potent morphogen during development of mammalian central nervous system. RA signaling is mediated by retinoid receptors, including RA receptors (RARs) and retinoid X receptors (RXRs), which are located in the nucleus and usually heterodimerized to function as transcription factors. To determine the RA signaling competence in developing rodent telencephalon, I first assayed whether different regions of developing telencephalon can differentially synthesize and respond to RA. To this end, I developed an electroporation-based technique to transfect a RA response element-regulated reporter gene into telencephalic explant tissues. The LGE (the striatal primodium) was demonstrated as the primary telencephalic region that synthesizes and responds to RA. Stronger transcriptional repression was found in the CTX (dorsal telencephalon) than in the LGE and MGE (ventral telencephalon) in the absence of RA. A ligand-dependent de-repression occurred in the LGE in the presence of retinol (a precursor of RA). The de-repression also was found in the CTX and MGE with RA treatment, which might be partly resulted from RA-induced auto-upregulation of RARβ. RARβ may mediate the RA-induced up-regulation of STEP in the LGE and MGE, as ectopic expression of RARβ1 in the CTX was sufficient to enhance STEP expression in response to RA, and null mutation of RARβ reduced STEP expression in the striatum. These results suggested RARβ□could be the major mediator for retinoid signaling in the developing striatum. The striatum is a major part of ventral telencephalon and plays a pivotal role in modulating psychomotor behavior. To establish a well-functional striatum, the compartmentalization of striosomes and matrix is a critical process during striatal development. It is still puzzled in how the striosomes and matrix compartments could be organized in the striatum. Given the selective expression of RARβ and RXR-gamma in the striatum, I examined whether the striatal compartments could be formed normally in mice lacking RARβ or RXR-gamma. Indeed, RARβ was required for compartment formation of the rostral striatum, as expression of striosomal markers were diminished and most of the striosomal cells disappeared in the rostral striatum of RARβ null mutants. In contrast to the RARβ-/- mutants, the reduction of striosomal marker gene expression, which is likely due to alteration in neurochemical phenotypes, was found only in the dorsolateral striatum of RXR-gamma-/- mutants. In addition, the role of ubiquitously expressed RXRβ in compartment formation of the striatum was also investigated. Although the striosomal pattern appeared to be normal in the striatum of RXRβ-/- mutants, the phenotype of RXRβ:RXR-gamma double knockout mice was resemble to that of RARβ-/- mice. Taken together, my study revealed the importance of RARβ in striatal development, and suggested the possible involvement of RARβ/RXRβ and RARβ/RXR-gamma heterodimers in compartment formation of the striatum.