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Genes Dev. 2005 Oct 1;19(19):2320-30.

Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy.

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  • 1Institute of Biochemistry and Institute of Physiological Chemistry, Biocenter of the University of Würzburg, D-97074 Würzburg, Germany.

Abstract

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.

PMID:
16204184
PMCID:
PMC1240041
DOI:
10.1101/gad.342005
[PubMed - indexed for MEDLINE]
Free PMC Article
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