ZFIN ID: ZDB-PUB-051012-2
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., and Fischer, U.
Date: 2005
Source: Genes & Development   19(19): 2320-2330 (Journal)
Registered Authors: Winkler, Christoph
Keywords: Survival motor neurons (SMN), U snRNP assembly, motoneuron, spinal muscular atrophy, zebrafish
MeSH Terms:
  • Animals
  • Axons/metabolism
  • Axons/pathology
  • Disease Models, Animal
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/pathology
  • Fibroblasts/metabolism
  • HeLa Cells
  • Humans
  • Muscular Atrophy, Spinal/genetics
  • Muscular Atrophy, Spinal/metabolism*
  • Muscular Atrophy, Spinal/pathology
  • Nerve Tissue Proteins/genetics
  • Nerve Tissue Proteins/metabolism*
  • RNA Interference*
  • RNA-Binding Proteins
  • Ribonucleoproteins, Small Nuclear/genetics
  • Ribonucleoproteins, Small Nuclear/metabolism*
  • Xenopus laevis
  • Zebrafish/embryology*
  • Zebrafish/genetics
PubMed: 16204184 Full text @ Genes & Dev.
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.