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Translational regulation of the human achaete-scute homologue-1 (hASH1) by fragile x-mental retardation protein (FMRP)

Item Type:Article
Title:Translational regulation of the human achaete-scute homologue-1 (hASH1) by fragile x-mental retardation protein (FMRP)
Creators Name:Faehling, M. and Mrowka, R. and Steege, A. and Kirschner, K.M. and Benko, E. and Foerstera, B. and Persson, P.B. and Thiele, B.J. and Meier, J.C. and Scholz, H.
Abstract:Fragile X syndrome is a common inherited cause of mental retardation that results from loss or mutation of the fragile X mental retardation protein (FMRP). In this study, we identified the mRNA of the basic helix-loop-helix transcription factor human achaete-scute homologue-1 (hASH1; ASCL1), which is required for normal development of the nervous system and has been implicated in the formation of neuroendocrine tumors, as a new FMRP target. Using a double-immuno-fluorescent staining technique we detected an overlapping pattern of both proteins in the hippocampus, temporal cortex, subventricular zone and cerebellum of newborn rats. Forced expression of FMRP and gene silencing by siRNA transfection revealed a positive correlation between the cellular protein levels of FMRP and hASH1. A luciferase reporter construct containing the 5'-untranslated region (UTR) of hASH1 mRNA was activated by the full-length FMRP, but not by naturally occurring truncated FMR-proteins, in transient co-transfections. The responsible cis-element was mapped by UV-cross-linking experiments and reporter mutagenesis assays to a (U)10-sequence located in the 5'-UTR of the hASH1 mRNA. Sucrose density gradient centrifugation revealed that hASH1 transcripts were translocated into a translationally active polysomal fraction upon transient transfection of HEK293 cells with FMRP, thus indicating translational activation of hASH1 mRNA. In conclusion, we identified hASH1 as a novel downstream target of FMRP. Improved translation efficiency of hASH1 mRNA by FMRP may represent an important regulatory switch in neuronal differentiation.
Keywords:Newborn Animals, Basic Helix-Loop-Helix Transcription Factors, Brain, Cell Differentiation, Fragile X Mental Retardation Protein, Fragile X Syndrome, Gene Expression Regulation, Neurons, Polyribosomes, Wistar Rats, Animals, Rats
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:4255-4266
Date:13 February 2009
Official Publication:https://doi.org/10.1074/jbc.M807354200
PubMed:View item in PubMed

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