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RESEARCH PAPER
1 Institute of Biochemistry and 2 Institute of Physiological Chemistry, Biocenter of the University of Würzburg, D-97074 Würzburg, Germany; 3 Institute of Zoology II, University of Karlsruhe, D-76131 Karlsruhe, Germany; 4 Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany
Spinal muscular atrophy (SMA) is a motoneuron disease caused by reduced levels of survival motoneuron (SMN) protein. Previous studies have assigned SMN to uridine-rich small nuclear ribonucleoprotein particle (U snRNP) assembly, splicing, transcription, and RNA localization. Here, we have used gene silencing to assess the effect of SMN protein deficiency on U snRNP metabolism in living cells and organisms. In HeLa cells, we show that reduction of SMN to levels found in SMA patients impairs U snRNP assembly. In line with this, induced silencing of SMN expression in Xenopus laevis or zebrafish arrested embryonic development. Under less severe knock-down conditions, zebrafish embryos proceeded through development yet exhibited dramatic SMA-like motor axon degeneration. The same was observed after silencing two other essential factors in the U snRNP assembly pathway, Gemin2 and pICln. Importantly, the injection of purified U snRNPs into either SMN- or Gemin2-deficient embryos of Xenopus and zebrafish prevented developmental arrest and motoneuron degeneration, respectively. These findings suggest that motoneuron degeneration in SMA patients is a direct consequence of impaired production of U snRNPs.
[Keywords: Survival motor neurons (SMN); U snRNP assembly; motoneuron; spinal muscular atrophy; zebrafish]
Received March 1, 2005; revised version accepted July 27, 2005.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.342005.
5 These authors contributed equally to this work.
E-MAIL utz.fischer{at}biozentrum.uni-wuerzburg.de; FAX 49-931-888-4028.
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