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Genes Dev
2005 Oct 01;1919:2320-30. doi: 10.1101/gad.342005.
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Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy.
Winkler C, Eggert C, Gradl D, Meister G, Giegerich M, Wedlich D, Laggerbauer B, Fischer U.
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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.
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Figure 3. SMN and Gemin2 are essential for the development of Xenopus embryos. (A) SiRNAs complementary to SMN or Gemin2, or nonspecific siRNAs were injected into X. laevis embryos, and survival was scored at gastrula (left column) or neurula (middle and right columns). Dead or developmentally arrested embryos display an abnormal outgrowth of white cell mass. (B) Western blot analysis of the SMN level in embryos treated with control (lanes 1-4) or SMN-siRNAs (lanes 5-8) in comparison to actin levels. Analyses of embryos that received a coinjection of U snRNPs (see also legend for Fig. 4 for details) are shown in lanes 9-12. Each lane represents an individual embryo. Relative SMN expression levels were estimated by densitometry in comparison to actin levels. (C) Quantification of the injection studies shown in A. Results are shown for two siRNA concentrations (2 and 0.2 μM) and two different siRNAs per target. The numbers of examined embryos (n) are indicated below each row.
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