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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.
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.
Appel,
Motoneuron fate specification revealed by patterned LIM homeobox gene expression in embryonic zebrafish.
1995, Pubmed
Appel,
Motoneuron fate specification revealed by patterned LIM homeobox gene expression in embryonic zebrafish.
1995,
Pubmed
Beattie,
Control of motor axon guidance in the zebrafish embryo.
2000,
Pubmed
Brahms,
Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein.
2001,
Pubmed
Branscombe,
PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins.
2001,
Pubmed
Bringmann,
Purification of the individual snRNPs U1, U2, U5 and U4/U6 from HeLa cells and characterization of their protein constituents.
1986,
Pubmed
Cartegni,
Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1.
2002,
Pubmed
Chisholm,
Conservation and divergence of axon guidance mechanisms.
1999,
Pubmed
Faustino,
Pre-mRNA splicing and human disease.
2003,
Pubmed
Friesen,
The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins.
2001,
Pubmed
Grimmler,
Phosphorylation regulates the activity of the SMN complex during assembly of spliceosomal U snRNPs.
2005,
Pubmed
Gubitz,
The SMN complex.
2004,
Pubmed
Hsieh-Li,
A mouse model for spinal muscular atrophy.
2000,
Pubmed
Jablonka,
Co-regulation of survival of motor neuron (SMN) protein and its interactor SIP1 during development and in spinal muscular atrophy.
2001,
Pubmed
Jablonka,
Gene targeting of Gemin2 in mice reveals a correlation between defects in the biogenesis of U snRNPs and motoneuron cell death.
2002,
Pubmed
Kambach,
Crystal structures of two Sm protein complexes and their implications for the assembly of the spliceosomal snRNPs.
1999,
Pubmed
Kashima,
A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy.
2003,
Pubmed
Kimmel,
Stages of embryonic development of the zebrafish.
1995,
Pubmed
,
Xenbase
Korenbrot,
Circadian rhythm and light regulate opsin mRNA in rod photoreceptors.
1989,
Pubmed
Krapivinsky,
Molecular characterization of a swelling-induced chloride conductance regulatory protein, pICln.
1994,
Pubmed
,
Xenbase
Kühl,
Dominant negative expression of a cytoplasmically deleted mutant of XB/U-cadherin disturbs mesoderm migration during gastrulation in Xenopus laevis.
1996,
Pubmed
,
Xenbase
Lefebvre,
Correlation between severity and SMN protein level in spinal muscular atrophy.
1997,
Pubmed
Lefebvre,
Identification and characterization of a spinal muscular atrophy-determining gene.
1995,
Pubmed
Lorson,
An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN.
2000,
Pubmed
Lorson,
A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy.
1999,
Pubmed
McGarry,
Geminin deficiency causes a Chk1-dependent G2 arrest in Xenopus.
2002,
Pubmed
,
Xenbase
McWhorter,
Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding.
2003,
Pubmed
Meister,
Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of spliceosomal UsnRNPs.
2002,
Pubmed
,
Xenbase
Meister,
Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln.
2001,
Pubmed
,
Xenbase
Meister,
Characterization of a nuclear 20S complex containing the survival of motor neurons (SMN) protein and a specific subset of spliceosomal Sm proteins.
2000,
Pubmed
Meister,
A multiprotein complex mediates the ATP-dependent assembly of spliceosomal U snRNPs.
2001,
Pubmed
,
Xenbase
Melançon,
Pathfinding by identified zebrafish motoneurons in the absence of muscle pioneers.
1997,
Pubmed
Monani,
The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy.
2000,
Pubmed
Pellizzoni,
Essential role for the SMN complex in the specificity of snRNP assembly.
2002,
Pubmed
Pellizzoni,
A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing.
1998,
Pubmed
Pillai,
Unique Sm core structure of U7 snRNPs: assembly by a specialized SMN complex and the role of a new component, Lsm11, in histone RNA processing.
2003,
Pubmed
Pu,
pICln inhibits snRNP biogenesis by binding core spliceosomal proteins.
1999,
Pubmed
,
Xenbase
Rossoll,
Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons.
2003,
Pubmed
Steward,
Translating axon guidance cues.
2002,
Pubmed
Strasswimmer,
Identification of survival motor neuron as a transcriptional activator-binding protein.
1999,
Pubmed
Tear,
Neuronal guidance. A genetic perspective.
1999,
Pubmed
Tessier-Lavigne,
The molecular biology of axon guidance.
1996,
Pubmed
Weinberg,
Developmental regulation of zebrafish MyoD in wild-type, no tail and spadetail embryos.
1996,
Pubmed
Will,
Spliceosomal UsnRNP biogenesis, structure and function.
2001,
Pubmed
Winkler,
Functional divergence of two zebrafish midkine growth factors following fish-specific gene duplication.
2003,
Pubmed
Zhang,
Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization.
2003,
Pubmed
