Human Molecular Genetics Advance Access published online on June 1, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi207
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1 Department of Neuroscience, Brown University, Providence, RI, 02912
* To whom correspondence should be addressed. Fragile X syndrome (FXS) is almost always caused by silencing of the FMR1 gene. The defects observed in FXS indicate that the normal FMR1 gene has a range of functions, and plays a particularly prominent role during development. However, the mechanisms regulating FMR1 expression in vivo are not known. Here, we have tested the role of the transcription factor AP-2
Received April 11, 2005
Revised May 26, 2005
Accepted May 26, 2005
Article
AP-2
selectively regulates Fragile X mental retardation-1 gene transcription during embryonic development
2 Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD, 20892
3 Department of Craniofacial Biology and Cell and Developmental Biology, UCHSC, Denver, CO 80262
4 Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030
5 Department of Genetics, St. Jude Children's Research Hospital, Memphis, TN, 38105
Justin R. Fallon, E-mail: Justin_Fallon{at};brown.edu
Abstract 
in regulating Fmr1 expression. Chromatin immunoprecipitation showed that AP-2 associates with the Fmr1 promoter in vivo. Furthermore, Fmr1 transcript levels are reduced>4-fold in homozygous null AP-2 mutant mice at embryonic day 18.5 as compared to normal littermates. Notably, AP-2 exhibits a strong gene dosage effect, with heterozygous mice showing 
2-fold reduction in Fmr1 levels. Examination of conditional AP-2 mutant mice indicates that this transcription factor plays a major role in regulating Fmr1 expression in embryos, but not in adults. We further investigated the role of AP-2 in the developmental regulation of Fmr1 expression using the Xenopus animal cap assay. Over-expression of a dominant-negative AP-2 in Xenopus embryos led to reduced Fmr1 levels. Moreover, exogenous wild-type AP-2 rescued Fmr1 expression in embryos where endogenous AP-2 had been suppressed. We conclude that AP-2 associates with the Fmr1 promoter in vivo and selectively regulates Fmr1 transcription during development.
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