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      Fragile X mental retardation protein FMRP and the RNA export factor NXF2 associate with and destabilize Nxf1 mRNA in neuronal cells.

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          Abstract

          Fragile X syndrome is caused by the inactivation of the X-linked FMR1 gene, leading to the loss of its encoded protein FMRP. Although macroorchidism and defects in neuronal architecture and function have been associated with lack of FMRP, the exact molecular mechanism underlying this disease remains unclear. We have reported previously that in the brain and testis of mice, FMRP specifically interacts with a distinct mRNA nuclear export factor NXF2 but not with its close relative NXF1, a ubiquitously expressed essential mRNA nuclear export factor. This interaction marked NXF2 as a putative functional partner of FMRP. Here, we demonstrate by immunoprecipitation and quantitative real-time RT-PCR that, in cultured mouse neuronal cells, both FMRP and NXF2 are present in Nxf1 mRNA-containing ribonucleoprotein particles. Further, we show that expression of NXF2 leads to the destabilization of Nxf1 mRNA and that this effect is abolished when Fmr1 expression is reduced by siRNA, arguing that both proteins collaborate to exert this effect. Importantly, these findings correlate well with our observations that in both mouse hippocampal neurons and male germ cells where the expression of FMRP and NXF2 is most prominent, the expression of NXF1 is relatively poorly expressed. Our studies thus identify Nxf1 mRNA as a likely biologically relevant in vivo target of both FMRP and NXF2 and implicate FMRP, in conjunction with NXF2, as a posttranscriptional regulator of a major mRNA export factor. Such regulation may prove important in the normal development and function of neurons as well as of male germ cells.

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proceedings of the National Academy of Sciences of the United States of America
          Proceedings of the National Academy of Sciences
          0027-8424
          0027-8424
          Jun 12 2007
          : 104
          : 24
          Affiliations
          [1 ] Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, 300 George Street, New Haven, CT 06511, USA.
          Article
          0700169104
          10.1073/pnas.0700169104
          1891223
          17548835
          e928750e-02ea-420b-8e63-9d41201c52cb
          History

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