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Frontiers in Biology

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ISSN 1674-7992(Online)

CN 11-5892/Q

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Front. Biol.    2015, Vol. 10 Issue (4) : 297-309    https://doi.org/10.1007/s11515-015-1368-9
REVIEW
A SteMNess perspective of survival motor neuron function: splicing factors in stem cell biology and disease
Stuart J. Grice,Ji-Long Liu()
MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK
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Abstract

Genome-wide analyses of metazoan messenger RNA (mRNA) species are unveiling the extensive transcriptional diversity generated by alternative splicing (AS). Research is also beginning to identify the splicing factors and AS events required to maintain the balance between stem cell renewal (i.e stemness properties) and differentiation. One set of proteins at the center of spliceosome biogenesis are the survival motor neuron (SMN) complex constituents, which have a critical role in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) in all cells. In this review we discuss what is currently known about how AS controls pluripotency and cell fate and consider how an increased requirement for splicing factors, including SMN, helps to maintain an enrichment of stem cell-specific AS events. Furthermore, we highlight studies showing that mutations in specific splicing factors can lead to the aberrant development, and cause targeted degeneration of the nervous system. Using SMN as an example, we discuss the perspective of how stem cell-specific changes in splicing factors can lead to developmental defects and the selective degeneration of particular tissues. Finally we consider the expanding role of SMN, and other splicing factors, in the regulation of gene expression in stem cell biology, thereby providing insight into a number of debilitating diseases.
Keywords stem cells      splicing      survival motor neuron (SMN)      spinal muscular atrophy (SMA)     
Corresponding Author(s): Ji-Long Liu   
Just Accepted Date: 20 July 2015   Online First Date: 05 August 2015    Issue Date: 14 August 2015
 Cite this article:   
Stuart J. Grice,Ji-Long Liu. A SteMNess perspective of survival motor neuron function: splicing factors in stem cell biology and disease[J]. Front. Biol., 2015, 10(4): 297-309.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-015-1368-9
https://academic.hep.com.cn/fib/EN/Y2015/V10/I4/297
Fig.1  The relationships between SMN and splicing function. The SMN complex is involved in the assembly of spliceosomal snRNPs, and the LSm non-coding RNP associated with histone mRNA processing. The SMN complex with the bound Sm proteins recruits cytoplasmic snRNAs and facilitates the formation of snRNA. The SMN complex, with the snRNPs, is transported into the nucleus. The final processing of the splicosomal snRNPs occurs in the Cajal body, before they are utilized in mRNA splicing. The snRNAs, along with many additional splicing factors facilitate both the removal of the introns and the processing of the mRNA. Cytoplasmic U7 snRNAs are also assembled by an SMN complex, and are also transported to the nucleus. These localize to the histone locus body (HLB). The storage of both the spliceosomal snRNPs and the LSm non-coding RNPs occurs in the cytoplasmic U-body, which is physically and functionally linked to the RNA stability and transport related P-Body.
Fig.2  SMN levels in Drosophila motor neurons and neuronal stem cells (neuroblasts). Motor neuron-specific GFP (UAS-CD8-GFP, red) and RFP (UAS-H2B-RFP; blue) using D42-GAL4. Cell body levels of SMN (green) in the majority of motor neurons (blue nuclei) are at a basal low level when compared to neuroblasts (arrow) and immature neurons within the CNS.
Fig.3  Distribution of SMN in mouse stem cells. (A, B and C) Immunofluorescent staining of SMN at late stage of blastocyst embryos, which produce embryonic stem cells (ESCs). The higher expression of SMN (A, green) is located in the region of inner cell mass (ICM, arrow), which expresses high level of pluripotent marker OCT4 (B, red). (D, E and F) Mouse ESCs with antibodies against SMN (D) and OCT4 (E). Scale bar= 25 μm. Courtesy of Wei-Fang Chang and Li-Ying Sung.
Fig.4  A model for tissue selectivity in SMA. (A) The intensity of the green depicts SMN enrichment in the developing neuroblasts is required for normal neurogenesis. SMN also aids the correct functioning of the differentiated motor circuit, which has lower levels of SMN. (B) The motor system may be particularly sensitive to moderate SMN reduction, while subclinical defects in neurogenesis may occur. During this period the nervous system is ill-equipped for normal function, leading to degeneration over time. (C) Multiple tissue defects occur when SMN is reduced to very low levels. Defects in peripheral tissues also impact on the health of the individual, which may also compound motor defects.
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