Transport kinetics of FMRP containing the I304N mutation of severe fragile X syndrome in neurites of living rat PC12 cells

Experimental Neurology
Mariëtte SchrierR Willemsen

Abstract

Lack of fragile X mental retardation protein (FMRP) causes the fragile X syndrome, a common form of inherited mental retardation. The syndrome usually results from the expansion of a CGG repeat in the FMR1 gene with consequent transcriptional silencing of FMR1. However, one missense mutation (Ile304Asn) was reported in the second KH domain of the protein involved in RNA binding. The protein containing this mutation showed an impaired function, leading to an extremely severe phenotype. In the present report, we have studied the role of FMRP I304N in living PC12 cells to better understand the (dys) function of this mutant FMRP. We have generated an FMR1 I304N-EGFP stably transfected PC12 cell line with an inducible expression system (Tet-On) for regulated expression of the FMRP I304N-EGFP fusion protein. After Dox-induction, FMRP I304N-EGFP was localized in the neurites of PC12 cells; however, no granules were formed as has been recently demonstrated for the normal FMRP. Time-lapse microscopy in combination with bleaching technology illustrated that although FMRP I304N-EGFP does not form visible granules, the transport into the neurites is microtubule dependent. Immunoprecipitation with antibodies against GFP demonstrates that FM...Continue Reading

Citations

Apr 30, 2005·Nature Reviews. Neuroscience·Claudia Bagni, William T Greenough
Aug 16, 2005·Genes, Brain, and Behavior·J C DarnellR B Darnell
Dec 17, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Marta E Soden, Lu Chen
Dec 6, 2008·Neurobiology of Disease·Topi A TervonenMaija L Castrén
Jun 10, 2011·Clinical Genetics·R WillemsenB A Oostra
Aug 22, 2006·Brain Research·Natalia DolzhanskayaRobert B Denman
May 26, 2009·Neurobiology of Disease·Josien LevengaFemke M S de Vrij
Aug 30, 2017·Proceedings of the National Academy of Sciences of the United States of America·Minato HiranoKentaro Yoshii
Sep 25, 2020·The Journal of Cell Biology·Ann L WozniakSteven A Weinman

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