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SMN in spinal muscular atrophy and snRNP biogenesis

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Abstract Ribonucleoprotein (RNP) complexes function in nearly every facet of cellular activity. The spliceosome is an essential RNP that accurately identifies introns and catalytically removes the intervening sequences, providing exquisite control of spatial, temporal, and developmental gene expressions. U‐snRNPs are the building blocks for the spliceosome. A significant amount of insight into the molecular assembly of these essential particles has recently come from a seemingly unexpected area of research: neurodegeneration. Survival motor neuron (SMN) performs an essential role in the maturation of snRNPs, while the homozygous loss of SMN1 results in the development of spinal muscular atrophy (SMA), a devastating neurodegenerative disease. In this review, the function of SMN is examined within the context of snRNP biogenesis and evidence is examined which suggests that the SMN functional defects in snRNP biogenesis may account for the motor neuron pathology observed in SMA. WIREs RNA 2011 2 546–564 DOI: 10.1002/wrna.76 This article is categorized under: RNA Interactions with Proteins and Other Molecules > RNA–Protein Complexes RNA Processing > Processing of Small RNAs RNA in Disease and Development > RNA in Disease

Survival motor neuron (SMN) protein subdomains. The amino acid number corresponding to the exon peptides and the size of the SMN protein is indicated above the red exon boxes. The SMN is 294 amino acids and runs at 38 kDa on Western blots. The relative sizes of the exons are diagrammed with the exon number below. Identified protein subdomains and associated functions are indicated. Below is an abbreviated list of proteins that interact with the SMN along with the approximate region of interaction.

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Proposed role for the survival motor neuron (SMN) in neurons involves a novel ribonucleoprotein (RNP) complex. Within axons, a pool of SMN exists that is not complexed with Sm proteins and the entire Gemin complex. Additional SMN–RNP forms that contain hnRNP‐Q and ‐R (blue) are ZPB (green) and β‐actin mRNA. The active transport of this complex results in the accumulation of β‐actin mRNA and protein at the distal end of the axon and at the neuromuscular junction (NMJ). In the spinal muscular atrophy (SMA; bottom panel), low levels of the SMN result in reduced levels of β‐actin accumulation and poorly developed NMJs.

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Overview of the survival motor neuron (SMN) functions in the assembly of mature spliceosome particles. Small nuclear RNAs (snRNAs) are transcribed via polymerase II‐dependent expression. The presence of the m7G cap initiates binding by the nuclear export complex consisting of PHAX, XPO1/CRM1, RAN, and both subunits of the cap‐binding complex (CBC). Upon entering the cytoplasm, the nuclear export complex dissociates. Within the cytoplasm, several complexes consisting of partially assembled, snRNA‐free Sm proteins reside in the cytoplasm: SmD1/SmD2; SmB/B′/SmD3; and SmE/SmF/SmG. Prior to binding the SMN complex, PRMT5 and PRMT7 specifically methylate the C‐terminal tails of SmB, SmD1, and SmD3, thereby enhancing the affinity for the SMN complex. The SMN/Gemin/unrip complex binds the methylated Sm complex, allowing the specific recruitment of snRNAs. The Sm complex is guided onto the Sm‐binding site on the snRNA by Gemin5 at which point the heptameric ring structure is formed. The SMN/Gemin/small nuclear ribonucleoprotein (snRNP) complex interacts with trimethylguanosine synthetase 1 (TGS1) which results in the hypermythylation of the m7G cap and the formation of the m3G cap. The nuclear import complex consisting of snurportin and importin‐β interacts with the m3G cap and the SMN complex and transports the entire complex into the nucleus. Entry into the nucleus results in the release of the import complex, the SMN complex, and the snRNP's initial transitions through the Cajal body.

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Pre‐mRNA splicing regulation of survival motor neuron (SMN) genes. SMN1 exclusively produces the full‐length form of the protein. A number of cis‐ and trans‐regulatory elements facilitate SMN Exon 7 inclusion. Positively acting factors are shown in the top panel, including various SR, SR‐like, and heterogeneous nuclear ribonucleoprotein (hnRNP) proteins (green), as well as putative splice enhancers (SE1–3) and Element 2. The short sequence motif ‘CAGACAA’ represents a high‐affinity SF2/ASF‐binding motif that is bound by SF2 only in the SMN1 context. The first ‘C’ position (+6) is altered in SMN2 to a ‘T’. The general splicing machinery is indicated (blue). The bottom panel represents the regulatory mechanisms governing SMN2 pre‐mRNA splicing. The SF2/ASF‐binding motif has been severely impaired by the introduction of a ‘T’ at the +6 position: ‘TAGACAA’. Additionally, this site is now bound efficiently by hnRNP‐A1 and is within an additionally regulatory element referred to as EXTINCT. Additional hnRNP‐A1‐binding sites have been identified within the flanking intron, including the ISS‐N1 regions. Collectively, these factors prevent the identification of the already weak splice sites flanking Exon 7 and promote high levels of exon skipping, ∼90%. A small, but important level (10%) of SMN2 transcripts include Exon 7 and therefore encodes a fully functional SMN protein.

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Genomic organization of the survival motor neuron (SMN) locus. SMN1 and SMN2 are present on a single region of the same chromosome: 5q11.2‐13.3. An evolutionarily recent genetic duplication of approximately 500 kb resulted in the duplication and inversion of the SMN and several flanking genes, including SERF1, NAIP, and GTF2H2. Initially, genes other than SMN were implicated in the spinal muscular atrophy (SMA) development because larger deletions frequently excised SMN and additional sequences. However, the detection of intragenic mutations within the SMN conclusively demonstrated that SMN was the only SMA‐determining gene. SMN1 and SMN2 are nearly identical and the regulatory mechanisms governing their promoters are essentially unchanged (Sp1, Ets sites, and many more). Methylation and histone regulation appear critical for the SMN expression. Five silent, nonpolymorphic nucleotide differences are indicated at the 3′ end of SMN1 (SMN1‐derived sequences are on the top; SMN2 sequences are at the bottom). The critical difference is within Exon 7 (a C–T transition). In the full‐length transcript, Exon 8 is entirely noncoding, while in the SMNΔ7 transcript, four additional amino acids are derived from the 5′ end of Exon 8.

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Intracellular localization of the survival motor neuron (SMN). An anti‐SMN monoclonal antibody (4B7) was used to specifically detect SMN (green) in the HeLa cells, while DAPI stained the nucleus. The SMN is present within discrete nuclear foci, often referred to as gems. These gems have been used as a surrogate marker for the overall SMN concentration as the gem numbers frequently correspond to the total intracellular SMN levels.

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SMN2 is a critical modifier of disease severity. The genomic organization of a typical unaffected individual contains two SMN1 and two SMN2 genes, one on each chromosome (5q). No individuals have been identified that lacked both SMN1 and SMN2, presumably because this would result in early embryonic lethality. As the SMN2 gene copy number increases in the SMN1‐null spinal muscular atrophy (SMA) patients, the disease severity tends to decrease. This is likely due to the low, residual level of full‐length SMN produced by each SMN2, approximately 10% per SMN2 copy. High SMN2 numbers have been observed in SMN1‐null individuals who are phenotypically normal, although in genetic terms are defined as having SMA.

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RNA in Disease and Development > RNA in Disease
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