Regulation of protocadherin gene expression by multiple neuron-restrictive silencer elements scattered in the gene cluster |
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Authors: | Yuen-Peng Tan Shaobing Li Xiao-Juan Jiang Wailin Loh Yik Khon Foo Chay-Boon Loh Qiurong Xu Wai-Hong Yuen Michael Jones Jianlin Fu Byrappa Venkatesh Wei-Ping Yu |
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Institution: | 1.Gene Regulation Laboratory, National Neuroscience Institute, 11 Jalan Tan Tock Seng, 308433 Singapore, 2.School of Life Sciences, Shandong University, Jinan, Shandong, China, 3.Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, 138673 and 4.Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Biopolis, 138648 Singapore |
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Abstract: | The clustered protocadherins are a subfamily of neuronal cell adhesion molecules that play an important role in development of the nervous systems in vertebrates. The clustered protocadherin genes exhibit complex expression patterns in the central nervous system. In this study, we have investigated the molecular mechanism underlying neuronal expression of protocadherin genes using the protocadherin gene cluster in fugu as a model. By in silico prediction, we identified multiple neuron-restrictive silencer elements (NRSEs) scattered in the fugu protocadherin cluster and demonstrated that these elements bind specifically to NRSF/REST in vitro and in vivo. By using a transgenic Xenopus approach, we show that these NRSEs regulate neuronal specificity of protocadherin promoters by suppressing their activity in non-neuronal tissues. We provide evidence that protocadherin genes that do not contain an NRSE in their 5′ intergenic region are regulated by NRSEs in the regulatory region of their neighboring genes. We also show that protocadherin clusters in other vertebrates such as elephant shark, zebrafish, coelacanth, lizard, mouse and human, contain different sets of multiple NRSEs. Taken together, our data suggest that the neuronal specificity of protocadherin cluster genes in vertebrates is regulated by the NRSE-NRSF/REST system. |
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