title: AP-2alpha selectively regulates fragile X mental retardation-1 gene transcription during embryonic development.
abstract: 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-2alpha in regulating Fmr1 expression. Chromatin immunoprecipitation showed that AP-2alpha associates with the Fmr1 promoter in vivo. Furthermore, Fmr1 transcript levels are reduced >4-fold in homozygous null AP-2alpha mutant mice at embryonic day 18.5 when compared with normal littermates. Notably, AP-2alpha exhibits a strong gene dosage effect, with heterozygous mice showing approximately 2-fold reduction in Fmr1 levels. Examination of conditional AP-2alpha 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-2alpha in the developmental regulation of Fmr1 expression using the Xenopus animal cap assay. Over-expression of a dominant-negative AP-2alpha in Xenopus embryos led to reduced Fmr1 levels. Moreover, exogenous wild-type AP-2alpha rescued Fmr1 expression in embryos where endogenous AP-2alpha had been suppressed. We conclude that AP-2alpha associates with the Fmr1 promoter in vivo and selectively regulates Fmr1 transcription during embryonic development.
authors.affiliation: Department of Neuroscience, Brown University, Providence, RI 02912, USA.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Lim
authors.forename: Anne B
authors.initials: AB
authors.lastname: Booker
authors.forename: Ting
authors.initials: T
authors.lastname: Luo
authors.forename: Trevor
authors.initials: T
authors.lastname: Williams
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Furuta
authors.forename: Oleg
authors.initials: O
authors.lastname: Lagutin
authors.forename: Guillermo
authors.initials: G
authors.lastname: Oliver
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Sargent
authors.forename: Justin R
authors.initials: JR
authors.lastname: Fallon
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D004247:DNA; D005600:Fragile X Syndrome / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology*; D014981:Xenopus
chemical_list: D004247:DNA