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Hum Mol Genet July 15, 2005; 14 (14): 2027-34.

AP-2alpha selectively regulates fragile X mental retardation-1 gene transcription during embryonic development.

Lim JH , Booker AB , Luo T , Williams T , Furuta Y , Lagutin O , Oliver G , Sargent TD , Fallon JR .

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.

PubMed ID: 15930016
Article link: Hum Mol Genet
Grant support: [+]
Genes referenced: chrd.1 fmr1 six3 tfap2a

Disease Ontology terms: fragile X syndrome

Article Images: [+] show captions

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