A SteMNess perspective of survival motor neuron function: splicing factors in stem cell biology and disease

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.

Key words： stem cells; splicing; survival motor neuron (SMN); spinal muscular atrophy (SMA)

Compliance with ethics guidelines

Stuart J Grice and Ji-long Liu declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors.

References

1 Barash Y, Calarco J A, Gao W, Pan Q, Wang X, Shai O, Blencowe B J, Frey B J (2010). Deciphering the splicing code. Nature, 465(7294): 53–59

PMID

2 Bäumer D, Lee S, Nicholson G, Davies J L, Parkinson N J, Murray L M, Gillingwater T H, Ansorge O, Davies K E, Talbot K (2009). Alternative splicing events are a late feature of pathology in a mouse model of spinal muscular atrophy. PLoS Genet, 5(12): e1000773

PMID

3 Beggs J D (2005). Lsm proteins and RNA processing. Biochem Soc Trans, 33(Pt 3): 433–438

PMID

4 Borg R, Cauchi R J (2014). GEMINs: potential therapeutic targets for spinal muscular atrophy? Front Neurosci, 8: 325

PMID

5 Boulisfane N, Choleza M, Rage F, Neel H, Soret J, Bordonné R (2011). Impaired minor tri-snRNP assembly generates differential splicing defects of U12-type introns in lymphoblasts derived from a type I SMA patient. Hum Mol Genet, 20(4): 641–648

PMID

6 Bricceno K V, Martinez T, Leikina E, Duguez S, Partridge T A, Chernomordik L V, Fischbeck K H, Sumner C J, Burnett B G (2014). Survival motor neuron protein deficiency impairs myotube formation by altering myogenic gene expression and focal adhesion dynamics. Hum Mol Genet, 23(18): 4745–4757

PMID

7 Burghes A H, Beattie C E (2009). Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nat Rev Neurosci, 10(8): 597–609

PMID

8 Burlet P, Huber C, Bertrandy S, Ludosky M A, Zwaenepoel I, Clermont O, Roume J, Delezoide A L, Cartaud J, Munnich A, Lefebvre S (1998). The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy. Hum Mol Genet, 7(12): 1927–1933

PMID

9 Carvalho T, Almeida F, Calapez A, Lafarga M, Berciano M T, Carmo-Fonseca M (1999). The spinal muscular atrophy disease gene product, SMN: A link between snRNP biogenesis and the Cajal (coiled) body. J Cell Biol, 147(4): 715–728

PMID

10 Cauchi R J ( 2010). SMN and Gemins: ‘we are family’ ... or are we?: insights into the partnership between Gemins and the spinal muscular atrophy disease protein SMN. BioEssays, 32: 1077–1089

11 Cauchi R J, Sanchez-Pulido L, Liu J L (2010). Drosophila SMN complex proteins Gemin2, Gemin3, and Gemin5 are components of U bodies. Exp Cell Res, 316(14): 2354–2364

PMID

12 Chang W F, Xu J, Chang C C, Yang S H, Li H Y, Hsieh-Li H M, Tsai M H, Wu S C, Cheng W T, Liu J L, Sung L Y (2015). SMN is required for the maintenance of embryonic stem cells and neuronal differentiation in mice. Brain Struct Funct, 220(3): 1539–1553

PMID

13 Chen C, Nott T J, Jin J, Pawson T (2011). Deciphering arginine methylation: Tudor tells the tale. Nat Rev Mol Cell Biol, 12(10): 629–642

PMID

14 Chen X, Xu H, Yuan P, Fang F, Huss M, Vega V B, Wong E, Orlov Y L, Zhang W, Jiang J, Loh Y H, Yeo H C, Yeo Z X, Narang V, Govindarajan K R, Leong B, Shahab A, Ruan Y, Bourque G, Sung W K, Clarke N D, Wei C L, Ng H H (2008). Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell, 133(6): 1106–1117

PMID

15 Coady T H, Lorson C L (2011). SMN in spinal muscular atrophy and snRNP biogenesis. Wiley Interdiscip Rev RNA, 2(4): 546–564

PMID

16 Cusin V, Clermont O, Gérard B, Chantereau D, Elion J (2003). Prevalence of SMN1 deletion and duplication in carrier and normal populations: implication for genetic counselling. J Med Genet, 40(4): e39

PMID

17 David C J, Manley J L (2010). Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev, 24(21): 2343–2364

PMID

18 Dixon J R, Jung I, Selvaraj S, Shen Y, Antosiewicz-Bourget J E, Lee A Y, Ye Z, Kim A, Rajagopal N, Xie W, Diao Y, Liang J, Zhao H, Lobanenkov V V, Ecker J R, Thomson J A, Ren B (2015). Chromatin architecture reorganization during stem cell differentiation. Nature, 518(7539): 331–336

PMID

19 Edery P, Marcaillou C, Sahbatou M, Labalme A, Chastang J, Touraine R, Tubacher E, Senni F, Bober M B, Nampoothiri S, Jouk P S, Steichen E, Berland S, Toutain A, Wise C A, Sanlaville D, Rousseau F, Clerget-Darpoux F, Leutenegger A L (2011). Association of TALS developmental disorder with defect in minor splicing component U4atac snRNA. Science, 332(6026): 240–243

PMID

20 Fallini C, Bassell G J, Rossoll W (2012). Spinal muscular atrophy: the role of SMN in axonal mRNA regulation. Brain Res, 1462: 81–92

PMID

21 Faustino N A, Cooper T A (2003). Pre-mRNA splicing and human disease. Genes Dev, 17(4): 419–437

PMID

22 Feng D, Xie J (2013). Aberrant splicing in neurological diseases. Wiley Interdiscip Rev RNA, 4(6): 631–649

PMID

23 Fischer U, Englbrecht C, Chari A (2011). Biogenesis of spliceosomal small nuclear ribonucleoproteins. Wiley Interdiscip Rev RNA, 2(5): 718–731

PMID

24 Fischer U, Liu Q, Dreyfuss G (1997). The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell, 90(6): 1023–1029

PMID

25 Forbes D J, Kirschner M W, Caput D, Dahlberg J E, Lund E (1984). Differential expression of multiple U1 small nuclear RNAs in oocytes and embryos of Xenopus laevis. Cell, 38(3): 681–689

PMID

26 Gabanella F, Butchbach M E, Saieva L, Carissimi C, Burghes A H, Pellizzoni L (2007). Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS ONE, 2(9): e921

PMID

27 Gabanella F, Carissimi C, Usiello A, Pellizzoni L (2005). The activity of the spinal muscular atrophy protein is regulated during development and cellular differentiation. Hum Mol Genet, 14(23): 3629–3642

PMID

28 Gabut M, Samavarchi-Tehrani P, Wang X, Slobodeniuc V, O’Hanlon D, Sung H K, Alvarez M, Talukder S, Pan Q, Mazzoni E O, Nedelec S, Wichterle H, Woltjen K, Hughes T R, Zandstra P W, Nagy A, Wrana J L, Blencowe B J (2011). An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming. Cell, 147(1): 132–146

PMID

29 Gan Q, Chepelev I, Wei G, Tarayrah L, Cui K, Zhao K, Chen X (2010). Dynamic regulation of alternative splicing and chromatin structure in Drosophila gonads revealed by RNA-seq. Cell Res, 20(7): 763–783

PMID

30 Ghosh S, Marchand V, Gáspár I, Ephrussi A (2012). Control of RNP motility and localization by a splicing-dependent structure in oskar mRNA. Nat Struct Mol Biol, 19(4): 441–449

PMID

31 Gogliotti R G, Quinlan K A, Barlow C B, Heier C R, Heckman C J, Didonato C J (2012). Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction. J Neurosci, 32(11): 3818–3829

PMID

32 Graubert T A, Shen D, Ding L, Okeyo-Owuor T, Lunn C L, Shao J, Krysiak K, Harris C C, Koboldt D C, Larson D E, McLellan M D, Dooling D J, Abbott R M, Fulton R S, Schmidt H, Kalicki-Veizer J, O’Laughlin M, Grillot M, Baty J, Heath S, Frater J L, Nasim T, Link D C, Tomasson M H, Westervelt P, DiPersio J F, Mardis E R, Ley T J, Wilson R K, Walter M J (2012). Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat Genet, 44(1): 53–57

PMID

33 Graveley B R (2011). Splicing up pluripotency. Cell, 147(1): 22–24

PMID

34 Graveley B R, Hertel K J, Maniatis T (2001). The role of U2AF35 and U2AF65 in enhancer-dependent splicing. RNA, 7(6): 806–818

PMID

35 Grice S J, Liu J L (2011). Survival motor neuron protein regulates stem cell division, proliferation, and differentiation in Drosophila. PLoS Genet, 7(4): e1002030

PMID

36 Grice S J, Sleigh J N, Liu J L, Sattelle D B (2011). Invertebrate models of spinal muscular atrophy: insights into mechanisms and potential therapeutics. BioEssays, 33: 956–965

37 Grice S J, Sleigh J N, Motley W W, Liu J L, Burgess R W, Talbot K, Cader M Z (2015). Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology. Hum Mol Genet, 24(15): 4397–4406

PMID

38 Halfar K, Rommel C, Stocker H, Hafen E (2001). Ras controls growth, survival and differentiation in the Drosophila eye by different thresholds of MAP kinase activity. Development, 128(9): 1687–1696

PMID

39 Hamilton G, Gillingwater T H (2013). Spinal muscular atrophy: going beyond the motor neuron. Trends Mol Med, 19(1): 40–50

PMID

40 Han H, Irimia M, Ross P J, Sung H K, Alipanahi B, David L, Golipour A, Gabut M, Michael I P, Nachman E N, Wang E, Trcka D, Thompson T, O’Hanlon D, Slobodeniuc V, Barbosa-Morais N L, Burge C B, Moffat J, Frey B J, Nagy A, Ellis J, Wrana J L, Blencowe B J (2013). MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. Nature, 498(7453): 241–245

PMID

41 Hayhurst M, Wagner A K, Cerletti M, Wagers A J, Rubin L L (2012). A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein. Dev Biol, 368(2): 323–334

PMID

42 He H, Liyanarachchi S, Akagi K, Nagy R, Li J, Dietrich R C, Li W, Sebastian N, Wen B, Xin B, Singh J, Yan P, Alder H, Haan E, Wieczorek D, Albrecht B, Puffenberger E, Wang H, Westman J A, Padgett R A, Symer D E, de la Chapelle A (2011). Mutations in U4atac snRNA, a component of the minor spliceosome, in the developmental disorder MOPD I. Science, 332(6026): 238–240

PMID

43 Hinas A, Larsson P, Avesson L, Kirsebom L A, Virtanen A, Söderbom F (2006). Identification of the major spliceosomal RNAs in Dictyostelium discoideum reveals developmentally regulated U2 variants and polyadenylated snRNAs. Eukaryot Cell, 5(6): 924–934

PMID

44 Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett C F, Krainer A R (2011). Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature, 478(7367): 123–126

PMID

45 Huen M S, Sy S M, Leung K M, Ching Y P, Tipoe G L, Man C, Dong S, Chen J (2010). SON is a spliceosome-associated factor required for mitotic progression. Cell Cycle, 9(13): 2679–2685

PMID

46 Hunter G, Aghamaleky Sarvestany A, Roche S L, Symes R C, Gillingwater T H (2014). SMN-dependent intrinsic defects in Schwann cells in mouse models of spinal muscular atrophy. Hum Mol Genet, 23(9): 2235–2250

PMID

47 Huo Q, Kayikci M, Odermatt P, Meyer K, Michels O, Saxena S, Ule J, Schümperli D (2014). Splicing changes in SMA mouse motoneurons and SMN-depleted neuroblastoma cells: evidence for involvement of splicing regulatory proteins. RNA Biol, 11(11): 1430–1446

PMID

48 Jia Y, Mu J C, Ackerman S L (2012). Mutation of a U2 snRNA gene causes global disruption of alternative splicing and neurodegeneration. Cell, 148(1–2): 296–308

PMID

49 Jodelka F M, Ebert A D, Duelli D M, Hastings M L (2010). A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Hum Mol Genet, 19(24): 4906–4917

PMID

50 Jones K W, Gorzynski K, Hales C M, Fischer U, Badbanchi F, Terns R M, Terns M P (2001). Direct interaction of the spinal muscular atrophy disease protein SMN with the small nucleolar RNA-associated protein fibrillarin. J Biol Chem, 276(42): 38645–38651

PMID

51 Jurica M S, Moore M J (2003). Pre-mRNA splicing: awash in a sea of proteins. Mol Cell, 12(1): 5–14

PMID

52 Kerins J A, Hanazawa M, Dorsett M, Schedl T (2010). PRP-17 and the pre-mRNA splicing pathway are preferentially required for the proliferation versus meiotic development decision and germline sex determination in Caenorhabditis elegans. Dev Dyn, 239: 1555–1572

53 Krastev D B, Slabicki M, Paszkowski-Rogacz M, Hubner N C, Junqueira M, Shevchenko A, Mann M, Neugebauer K M, Buchholz F (2011). A systematic RNAi synthetic interaction screen reveals a link between p53 and snoRNP assembly. Nat Cell Biol, 13(7): 809–818

PMID

54 Laggerbauer B, Liu S, Makarov E, Vornlocher H P, Makarova O, Ingelfinger D, Achsel T, Lührmann R (2005). The human U5 snRNP 52K protein (CD2BP2) interacts with U5-102K (hPrp6), a U4/U6.U5 tri-snRNP bridging protein, but dissociates upon tri-snRNP formation. RNA, 11(5): 598–608

PMID

55 Lanner F, Rossant J (2010). The role of FGF/Erk signaling in pluripotent cells. Development, 137(20): 3351–3360

PMID

56 Le T T, McGovern V L, Alwine I E, Wang X, Massoni-Laporte A, Rich M M, Burghes A H (2011). Temporal requirement for high SMN expression in SMA mice. Hum Mol Genet, 20(18): 3578–3591

PMID

57 Lee L, Davies S E, Liu J L (2009). The spinal muscular atrophy protein SMN affects Drosophila germline nuclear organization through the U body-P body pathway. Dev Biol, 332(1): 142–155

PMID

58 Lee S, Sayin A, Cauchi R J, Grice S, Burdett H, Baban D, van den Heuvel M (2008). Genome-wide expression analysis of a spinal muscular atrophy model: towards discovery of new drug targets. PLoS ONE, 3(1): e1404

PMID

59 Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Le Paslier D, Frézal J, Cohen D, Weissenbach J, Munnich A, Melki J (1995). Identification and characterization of a spinal muscular atrophy-determining gene. Cell, 80(1): 155–165

PMID

60 Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, Dreyfuss G, Melki J (1997). Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet, 16(3): 265–269

PMID

61 Lefebvre S, Burlet P, Viollet L, Bertrandy S, Huber C, Belser C, Munnich A (2002). A novel association of the SMN protein with two major non-ribosomal nucleolar proteins and its implication in spinal muscular atrophy. Hum Mol Genet, 11(9): 1017–1027

PMID

62 Liu J L, Gall J G (2007). U bodies are cytoplasmic structures that contain uridine-rich small nuclear ribonucleoproteins and associate with P bodies. Proc Natl Acad Sci USA, 104(28): 11655–11659

PMID

63 Liu J L, Murphy C, Buszczak M, Clatterbuck S, Goodman R, Gall J G (2006). The Drosophila melanogaster Cajal body. J Cell Biol, 172(6): 875–884

PMID

64 Liu J L, Wu Z, Nizami Z, Deryusheva S, Rajendra T K, Beumer K J, Gao H, Matera A G, Carroll D, Gall J G (2009). Coilin is essential for Cajal body organization in Drosophila melanogaster. Mol Biol Cell, 20(6): 1661–1670

PMID

65 Liu Q, Dreyfuss G (1996). A novel nuclear structure containing the survival of motor neurons protein. EMBO J, 15(14): 3555–3565

PMID

66 Livyatan I, Meshorer E (2013). SON sheds light on RNA splicing and pluripotency. Nat Cell Biol, 15(10): 1139–1140

PMID

67 Loh Y H, Wu Q, Chew J L, Vega V B, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong K Y, Sung K W, Lee C W, Zhao X D, Chiu K P, Lipovich L, Kuznetsov V A, Robson P, Stanton L W, Wei C L, Ruan Y, Lim B, Ng H H (2006). The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet, 38(4): 431–440

PMID

68 Lorson C L, Androphy E J (2000). An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum Mol Genet, 9(2): 259–265

PMID

69 Lotti F, Imlach W L, Saieva L, Beck E S, Hao T, Li D K, Jiao W, Mentis G Z, Beattie C E, McCabe B D, Pellizzoni L (2012). An SMN-dependent U12 splicing event essential for motor circuit function. Cell, 151(2): 440–454

PMID

70 Lund E, Kahan B, Dahlberg J E (1985). Differential control of U1 small nuclear RNA expression during mouse development. Science, 229(4719): 1271–1274

PMID

71 Martínez-Hernández R, Bernal S, Also-Rallo E, Alías L, Barceló M J, Hereu M, Esquerda J E, Tizzano E F (2013). Synaptic defects in type I spinal muscular atrophy in human development. J Pathol, 229(1): 49–61

PMID

72 Maurer-Stroh S, Dickens N J, Hughes-Davies L, Kouzarides T, Eisenhaber F, Ponting C P (2003). The Tudor domain ‘Royal Family’: Tudor, plant Agenet, Chromo, PWWP and MBT domains. Trends Biochem Sci, 28(2): 69–74

PMID

73 Mayshar Y, Rom E, Chumakov I, Kronman A, Yayon A, Benvenisty N (2008). Fibroblast growth factor 4 and its novel splice isoform have opposing effects on the maintenance of human embryonic stem cell self-renewal. Stem Cells, 26(3): 767–774

PMID

74 McGivern J V, Patitucci T N, Nord J A, Barabas M E, Stucky C L, Ebert A D (2013). Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production. Glia, 61(9): 1418–1428

PMID

75 Monani U R, Coovert D D, Burghes A H (2000). Animal models of spinal muscular atrophy. Hum Mol Genet, 9(16): 2451–2457

PMID

76 Morency E, Sabra M, Catez F, Texier P, Lomonte P (2007). A novel cell response triggered by interphase centromere structural instability. J Cell Biol, 177(5): 757–768

PMID

77 Neumüller R A, Richter C, Fischer A, Novatchkova M, Neumüller K G, Knoblich J A (2011). Genome-wide analysis of self-renewal in Drosophila neural stem cells by transgenic RNAi. Cell Stem Cell, 8(5): 580–593

PMID

78 Niwa H, Miyazaki J, Smith A G (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet, 24(4): 372–376

PMID

79 O’Reilly D, Dienstbier M, Cowley S A, Vazquez P, Drozdz M, Taylor S, James W S, Murphy S (2013). Differentially expressed, variant U1 snRNAs regulate gene expression in human cells. Genome Res, 23(2): 281–291

PMID

80 Ohta S, Nishida E, Yamanaka S, Yamamoto T (2013). Global splicing pattern reversion during somatic cell reprogramming. Cell Reports, 5(2): 357–366

PMID

81 Ozsolak F, Milos P M (2011). RNA sequencing: advances, challenges and opportunities. Nat Rev Genet, 12(2): 87–98

PMID

82 Patel A A, Steitz J A (2003). Splicing double: insights from the second spliceosome. Nat Rev Mol Cell Biol, 4(12): 960–970

PMID

83 Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G (1998). A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell, 95(5): 615–624

PMID

84 Praveen K, Wen Y, Matera A G (2012). A Drosophila model of spinal muscular atrophy uncouples snRNP biogenesis functions of survival motor neuron from locomotion and viability defects. Cell Reports, 1(6): 624–631

PMID

85 Ruggiu M, McGovern V L, Lotti F, Saieva L, Li D K, Kariya S, Monani U R, Burghes A H, Pellizzoni L (2012). A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in spinal muscular atrophy. Mol Cell Biol, 32(1): 126–138

PMID

86 Sabra M, Texier P, El Maalouf J, Lomonte P (2013). The Tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated lysine 79 of histone H3. J Cell Sci, 126(Pt 16): 3664–3677

PMID

87 Salomonis N, Schlieve C R, Pereira L, Wahlquist C, Colas A, Zambon A C, Vranizan K, Spindler M J, Pico A R, Cline M S, Clark T A, Williams A, Blume J E, Samal E, Mercola M, Merrill B J, Conklin B R (2010). Alternative splicing regulates mouse embryonic stem cell pluripotency and differentiation. Proc Natl Acad Sci USA, 107(23): 10514–10519

PMID

88 Salzler H R, Tatomer D C, Malek P Y, McDaniel S L, Orlando A N, Marzluff W F, Duronio R J (2013). A sequence in the Drosophila H3-H4 Promoter triggers histone locus body assembly and biosynthesis of replication-coupled histone mRNAs. Dev Cell, 24(6): 623–634

PMID

89 Scamborova P, Wong A, Steitz J A (2004). An intronic enhancer regulates splicing of the twintron of Drosophila melanogaster prospero pre-mRNA by two different spliceosomes. Mol Cell Biol, 24(5): 1855–1869

PMID

90 Shafey D, Côté P D, Kothary R (2005). Hypomorphic Smn knockdown C2C12 myoblasts reveal intrinsic defects in myoblast fusion and myotube morphology. Exp Cell Res, 311(1): 49–61

PMID

91 Shirai C L, Ley J N, White B S, Kim S, Tibbitts J, Shao J, Ndonwi M, Wadugu B, Duncavage E J, Okeyo-Owuor T, Liu T, Griffith M, McGrath S, Magrini V, Fulton R S, Fronick C, O’Laughlin M, Graubert T A, Walter M J (2015). Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell, 27(5): 631–643

PMID

92 Sierra-Montes J M, Pereira-Simon S, Smail S S, Herrera R J (2005). The silk moth Bombyx mori U1 and U2 snRNA variants are differentially expressed. Gene, 352: 127–136

PMID

93 Sleigh J N, Barreiro-Iglesias A, Oliver P L, Biba A, Becker T, Davies K E, Becker C G, Talbot K (2014a). Chondrolectin affects cell survival and neuronal outgrowth in in vitro and in vivo models of spinal muscular atrophy. Hum Mol Genet, 23(4): 855–869

PMID

94 Sleigh J N, Gillingwater T H, Talbot K (2011). The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy. Dis Model Mech, 4(4): 457–467

PMID

95 Sleigh J N, Grice S J, Burgess R W, Talbot K, Cader M Z (2014b). Neuromuscular junction maturation defects precede impaired lower motor neuron connectivity in Charcot-Marie-Tooth type 2D mice. Hum Mol Genet, 23(10): 2639–2650

PMID

96 Sleigh J N, Grice S J, Davies K E, Talbot K (2013). Spinal muscular atrophy at the crossroads of basic science and therapy. Neuromuscul Disord, 23(1): 96

PMID

97 Sousa-Nunes R, Cheng L Y, Gould A P (2010). Regulating neural proliferation in the Drosophila CNS. Curr Opin Neurobiol, 20(1): 50–57

PMID

98 Sterne-Weiler T, Sanford J R (2014). Exon identity crisis: disease-causing mutations that disrupt the splicing code. Genome Biol, 15(1): 201

PMID

99 Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861–872

PMID

100 Thornton G K, Woods C G (2009). Primary microcephaly: do all roads lead to Rome? Trends Genet, 25(11): 501–510

PMID

101 Tisdale S, Lotti F, Saieva L, Van Meerbeke J P, Crawford T O, Sumner C J, Mentis G Z, Pellizzoni L (2013). SMN is essential for the biogenesis of U7 small nuclear ribonucleoprotein and 3′-end formation of histone mRNAs. Cell Reports, 5(5): 1187–1195

PMID

102 Turunen J J, Niemelä E H, Verma B, Frilander M J (2013). The significant other: splicing by the minor spliceosome. Wiley Interdiscip Rev RNA, 4(1): 61–76

PMID

103 Valadkhan S, Jaladat Y (2010). The spliceosomal proteome: at the heart of the largest cellular ribonucleoprotein machine. Proteomics, 10(22): 4128–4141

PMID

104 Venables J P, Lapasset L, Gadea G, Fort P, Klinck R, Irimia M, Vignal E, Thibault P, Prinos P, Chabot B, Abou Elela S, Roux P, Lemaitre J M, Tazi J (2013). MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. Nat Commun, 4: 2480

PMID

105 Verheggen C, Mouaikel J, Thiry M, Blanchard J M, Tollervey D, Bordonné R, Lafontaine D L, Bertrand E (2001). Box C/D small nucleolar RNA trafficking involves small nucleolar RNP proteins, nucleolar factors and a novel nuclear domain. EMBO J, 20(19): 5480–5490

PMID

106 Wahl M C, Will C L, Lührmann R (2009). The spliceosome: design principles of a dynamic RNP machine. Cell, 136(4): 701–718

PMID

107 Wan L, Battle D J, Yong J, Gubitz A K, Kolb S J, Wang J, Dreyfuss G (2005). The survival of motor neurons protein determines the capacity for snRNP assembly: biochemical deficiency in spinal muscular atrophy. Mol Cell Biol, 25(13): 5543–5551

PMID

108 Wang C, Wilson-Berry L, Schedl T, Hansen D(2012). TEG-1 CD2BP2 regulates stem cell proliferation and sex determination in the C. elegans germ line and physically interacts with the UAF-1 U2AF65 splicing factor. Deve Dyn, 241: 505–521

109 Wang E T, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore S F, Schroth G P, Burge C B (2008). Alternative isoform regulation in human tissue transcriptomes. Nature, 456(7221): 470–476

PMID

110 Will C L, Schneider C, Reed R, Lührmann R (1999). Identification of both shared and distinct proteins in the major and minor spliceosomes. Science, 284(5422): 2003–2005

PMID

111 Winkler C, Eggert C, Gradl D, Meister G, Giegerich M, Wedlich D, Laggerbauer B, Fischer U (2005). Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy. Genes Dev, 19(19): 2320–2330

PMID

112 Wishart T M, Huang J P, Murray L M, Lamont D J, Mutsaers C A, Ross J, Geldsetzer P, Ansorge O, Talbot K, Parson S H, Gillingwater T H (2010). SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy. Hum Mol Genet, 19(21): 4216–4228

PMID

113 Wollnik B (2010). A common mechanism for microcephaly. Nat Genet, 42(11): 923–924

PMID

114 Wu J Q, Habegger L, Noisa P, Szekely A, Qiu C, Hutchison S, Raha D, Egholm M, Lin H, Weissman S, Cui W, Gerstein M, Snyder M (2010). Dynamic transcriptomes during neural differentiation of human embryonic stem cells revealed by short, long, and paired-end sequencing. Proc Natl Acad Sci USA, 107(11): 5254–5259

PMID

115 Yeo G W, Xu X, Liang T Y, Muotri A R, Carson C T, Coufal N G, Gage F H (2007). Alternative splicing events identified in human embryonic stem cells and neural progenitors. PLOS Comput Biol, 3(10): 1951–1967

PMID

116 Younis I, Dittmar K, Wang W, Foley S W, Berg M G, Hu K Y, Wei Z, Wan L, Dreyfuss G (2013). Minor introns are embedded molecular switches regulated by highly unstable U6atac snRNA. eLife, 2: e00780

PMID

117 Zhang Z, Lotti F, Dittmar K, Younis I, Wan L, Kasim M, Dreyfuss G (2008). SMN deficiency causes tissue-specific perturbations in the repertoire of snRNAs and widespread defects in splicing. Cell, 133(4): 585–600

PMID

118 Zhang Z, Pinto A M, Wan L, Wang W, Berg M G, Oliva I, Singh L N, Dengler C, Wei Z, Dreyfuss G (2013). Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc Natl Acad Sci USA, 110(48): 19348–19353

PMID