Regulation of protocadherin gene expression by multiple neuron-restrictive silencer elements scattered in the gene cluster.
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.
Tan
Yuen-Peng
YP
Gene Regulation Laboratory, National Neuroscience Institute, Singapore.
Li
Shaobing
S
Jiang
Xiao-Juan
XJ
Loh
Wailin
W
Foo
Yik Khon
YK
Loh
Chay-Boon
CB
Xu
Qiurong
Q
Yuen
Wai-Hong
WH
Jones
Michael
M
Fu
Jianlin
J
Venkatesh
Byrappa
B
Yu
Wei-Ping
WP
D000818:Animals; D015820:Cadherins / Q000235:genetics*; D002460:Cell Line; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D005810:Multigene Family; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D037941:Silencer Elements, Transcriptional; D023741:Takifugu / Q000235:genetics; D014982:Xenopus laevis; D015027:Zebrafish / Q000235:genetics
D015820:Cadherins
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