Article

Molecular functions of the SMN complex. J Child Neurol

Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Journal of Child Neurology (Impact Factor: 1.67). 09/2007; 22(8):990-4. DOI: 10.1177/0883073807305666
Source: PubMed

ABSTRACT The SMN complex is essential for the biogenesis of spliceosomal small nuclear ribonucleoproteins and likely functions in the assembly, metabolism, and transport of a diverse number of other ribonucleoproteins. Specifically, the SMN complex assembles 7 Sm proteins into a core structure around a highly conserved sequence of ribonucleic acid (RNA) found in small nuclear RNAs. The complex recognizes specific sequences and structural features of small nuclear RNAs and Sm proteins and assembles small nuclear ribonucleoproteins in a stepwise fashion. In addition to the SMN protein, the SMN complex contains 7 additional proteins known as Gemin2-8, each likely to play a role in ribonucleoprotein biogenesis. This review focuses on the current understanding of the mechanism of the role of the SMN complex in small nuclear ribonucleoprotein assembly and considers the relationship of this function to spinal muscular atrophy.

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    • "Western blot analysis revealed that profilin II (a and b) levels were not altered when Smn levels decreased. Furthermore, we examined levels of other SMN binding partners, gemin 2 and gemin 5. Gemins are proteins that form a complex with SMN necessary for snRNP assembly and splicing (Paushkin et al., 2002; Kolb et al., 2007). Gemin 2 is an SMN binding protein that decreases in cultured cells and in mice when SMN is decreased (Wang and Dreyfuss, 2001; Feng et al., 2005; Gabanella et al., 2007). "
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    ABSTRACT: The actin-binding protein plastin 3 (PLS3) has been identified as a modifier of the human motoneuron disease spinal muscular atrophy (SMA). SMA is caused by decreased levels of the survival motor neuron protein (SMN) and in its most severe form causes death in infants and young children. To understand the mechanism of PLS3 in SMA, we have analyzed pls3 RNA and protein in zebrafish smn mutants. We show that Pls3 protein levels are severely decreased in smn(-/-) mutants without a reduction in pls3 mRNA levels. Moreover, we show that both pls3 mRNA and protein stability are unaffected when Smn is reduced. This indicates that SMN affects PLS3 protein production. We had previously shown that, in smn mutants, the presynaptic protein SV2 is decreased at neuromuscular junctions. Transgenically driving human PLS3 in motoneurons rescues the decrease in SV2 expression. To determine whether PLS3 could also rescue function, we performed behavioral analysis on smn mutants and found that they had a significant decrease in spontaneous swimming and turning. Driving PLS3 transgenically in motoneurons rescued both of these defects. These data show that PLS3 protein levels are dependent on SMN and that PLS3 is able to rescue the neuromuscular defects and corresponding movement phenotypes caused by low levels of Smn suggesting that decreased PLS3 contributes to SMA motor phenotypes.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2012; 32(15):5074-84. DOI:10.1523/JNEUROSCI.5808-11.2012 · 6.75 Impact Factor
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    • "In our screen, we found that the down-regulation of six out of the seven Sm proteins results in an NPC disassembly defect and abnormal NPC distribution. We also observed similar phenotypes following down-regulation of SMN-1, which is involved in Sm protein complex assembly into snRNPs (Kolb et al., 2007). In contrast, efficient down-regulation of other core components of the spliceosome did not affect NPC disassembly or distribution. "
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    ABSTRACT: Nuclear pore complexes (NPCs) are large macromolecular structures embedded in the nuclear envelope (NE), where they facilitate exchange of molecules between the cytoplasm and the nucleoplasm. In most cell types, NPCs are evenly distributed around the NE. However, the mechanisms dictating NPC distribution are largely unknown. Here, we used the model organism Caenorhabditis elegans to identify genes that affect NPC distribution during early embryonic divisions. We found that down-regulation of the Sm proteins, which are core components of the spliceosome, but not down-regulation of other splicing factors, led to clustering of NPCs. Down-regulation of Sm proteins also led to incomplete disassembly of NPCs during mitosis, but had no effect on lamina disassembly, suggesting that the defect in NPC disassembly was not due to a general defect in nuclear envelope breakdown. We further found that these mitotic NPC remnants persisted on an ER membrane that juxtaposes the mitotic spindle. At the end of mitosis, the remnant NPCs moved toward the chromatin and the reforming NE, where they ultimately clustered by forming membrane stacks perforated by NPCs. Our results suggest a novel, splicing-independent, role for Sm proteins in NPC disassembly, and point to a possible link between NPC disassembly in mitosis and NPC distribution in the subsequent interphase.
    Developmental Biology 03/2012; 365(2):445-57. DOI:10.1016/j.ydbio.2012.02.036 · 3.64 Impact Factor
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    • "When in the nucleus, it is often localized in " gems " which are closely related to and located near Cajal bodies, major sites of nuclear RNA transcription and processing (Liu and Dreyfuss, 1996). SMN forms a complex with Gemins 2-8 and unrip and this complex regulates the assembly of small nuclear ribonuclear proteins (snRNPs) (reviewed in Kolb et al., 2007; "
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    ABSTRACT: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes degeneration of α-motor neurons. Frequently, muscle weakness is very severe causing affected infants to die before reaching two years of age, but mild forms of the disease can be characterized by relatively static muscle weakness for many years. SMA is caused by recessive mutations of the SMN1 gene, but all patients retain at least one copy of SMN2, a similar gene capable of producing low levels of full-length SMN protein. No treatments currently exist for SMA patients, but the identification of therapeutic targets and the development of suitable animal models for preclinical testing have resulted in increased drug development efforts in the past ten years. Here, we review the current status of many of these programs, including those designed to activate SMN2 gene expression, modulate splicing of SMN2 preRNAs, stabilize SMN protein, replace SMN1, provide neuroprotective support, and transplant neural cells.
    Discovery medicine 10/2011; 12(65):291-305. · 3.50 Impact Factor
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