Human Molecular Genetics Advance Access originally published online on June 1, 2005
Human Molecular Genetics 2005 14(14):2027-2034; doi:10.1093/hmg/ddi207
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AP-2
selectively regulates fragile X mental retardation-1 gene transcription during embryonic development
1Department of Neuroscience, Brown University, PO Box 1953, 190 Thayer Street, Providence, RI 02912, USA, 2Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD 20892, USA, 3Department of Craniofacial Biology and Cell and Developmental Biology, UCHSC, Denver, CO 80262, USA, 4Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA and 5Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA
* To whom correspondence should be addressed. Tel: +1 4018639308; Fax: +1 4018631074; Email: justin_fallon{at}brown.edu
Received April 11, 2005; Accepted May 26, 2005
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
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 when compared with 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 embryonic development.
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