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

• Published in: Genes & development Vol. 19; no. 19; pp. 2320 - 2330
• Main Authors: Winkler, Christoph, Eggert, Christian, Gradl, Dietmar, Meister, Gunter, Giegerich, Marieke, Wedlich, Doris, Laggerbauer, Bernhard, Fischer, Utz
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.10.2005
• Subjects: Animals; Axons - metabolism; Axons - pathology; Danio rerio; Disease Models, Animal; Embryo, Nonmammalian - embryology; Embryo, Nonmammalian - pathology; Fibroblasts - metabolism; Freshwater; HeLa Cells; Humans; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Research Papers; Ribonucleoproteins, Small Nuclear - genetics; Ribonucleoproteins, Small Nuclear - metabolism; RNA Interference; RNA-Binding Proteins; Xenopus laevis; Zebrafish - embryology; Zebrafish - genetics
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.342005

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.