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PTB was initially discovered as a polypyrimidine tract-binding protein (hence the name), which corresponds to a specific RNA-binding protein associated with heterogeneous ribonucleoprotein particle (hnRNP I). The PTB family consists of three members in mammalian genomes, with PTBP1 (PTB) expressed in most cell types, PTBP2 (also known as nPTB or brPTB) exclusively found in the nervous system, and PTBP3 (also known as ROD1) predominately detected in immune cells. During neural development, PTB is down-regulated, which induces nPTB, and the expression of both PTB and nPTB becomes diminished when neurons mature. This programed switch, which largely takes place at the splicing level, is critical for the development of the nervous system, with PTB playing a central role in neuronal induction and nPTB guarding neuronal maturation. Remarkably, sequential knockdown of PTB and nPTB has been found to be necessary and sufficient to convert non-neuronal cells to the neuronal lineage. These findings, coupled with exquisite understanding of the molecular circuits regulated by these RNA-binding proteins, establish a critical foundation for their future applications in regenerative medicine.
Amir-Ahmady B, Boutz PL, Markovtsov V, Phillips ML, Black DL, (2005) Exon repression by polypyrimidine tract binding protein.RNA 11:699-716
Ashiya M, Grabowski PJ, (1997) A neuron-specific splicing switch mediated by an array of pre-mRNA repressor sites: evidence of a regulatory role for the polypyrimidine tract binding protein and a brain-specific PTB counterpart.RNA 3:996-1015
Black DL, (2003) Mechanisms of alternative pre-messenger RNA splicing.Annu Rev Biochem 72:291-336
Boutz PL, Chawla G, Stoilov P, Black DL, (2007) MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development.Genes Dev 21:71-84
Boutz PL, Stoilov P, Li Q, Lin CH, Chawla G, Ostrow K, Shiue L, Ares MJr, Black DL, (2007) A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons.Genes Dev 21:1636-1652
Busch A, Hertel KJ, (2012) Evolution of SR protein and hnRNP splicing regulatory factors.Wiley Interdiscip Rev RNA 3:1-12
Castelo-Branco P, Furger A, Wollerton M, Smith C, Moreira A, Proudfoot N, (2004) Polypyrimidine tract binding protein modulates efficiency of polyadenylation.Mol Cell Biol 24:4174-4183
Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, Conlon FL, Wang DZ, (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation.Nat Genet 38:228-233
Chou MY, Underwood JG, Nikolic J, Luu MH, Black DL, (2000) Multisite RNA binding and release of polypyrimidine tract binding protein during the regulation of c-src neural-specific splicing.Mol Cell 5:949-957
Corrionero A, Valcarcel J, (2009) RNA processing: redrawing the map of charted territory.Mol Cell 36:918-919
Coutinho-Mansfield GC, Xue Y, Zhang Y, Fu XD, (2007) PTB/nPTB switch: a post-transcriptional mechanism for programming neuronal differentiation.Genes Dev 21:1573-1577
Dowdy SF, (2017) Overcoming cellular barriers for RNA therapeutics.Nat Biotechnol 35:222-229
Ebrahimi B, (2016) Chemicals as the sole transformers of cell fate.Int J Stem Cells 9:9-20
Fu XD, Ares MJr, (2014) Context-dependent control of alternative splicing by RNA-binding proteins.Nat Rev Genet 15:689-701
Gao Z, Ure K, Ding P, Nashaat M, Yuan L, Ma J, Hammer RE, Hsieh J, (2011) The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells.J Neurosci 31:9772-9786
Gao L, Guan W, Wang M, Wang H, Yu J, Liu Q, Qiu B, Yu Y, Ping Y, Bian X, Shen L, Pei G, (2017) Direct generation of human neuronal cells from adult astrocytes by small molecules.Stem Cell Rep 8:538-547
Garcia-Blanco MA, Jamison SF, Sharp PA, (1989) Identification and purification of a 62,000-dalton protein that binds specifically to the polypyrimidine tract of introns.Genes Dev 3:1874-1886
Gerstberger S, Hafner M, Tuschl T, (2014) A census of human RNA-binding proteins.Nat Rev Genet 15:829-845
Ghetti A, Pinol-Roma S, Michael WM, Morandi C, Dreyfuss G, (1992) hnRNP I, the polypyrimidine tract-binding protein: distinct nuclear localization and association with hnRNAs.Nucleic Acids Res 20:3671-3678
Goldman SA, (2016) Stem and progenitor cell-based therapy of the central nervous system: hopes, hype, and wishful thinking.Cell Stem Cell 18:174-188
Gotz M, Barde YA, (2005) Radial glial cells defined and major intermediates between embryonic stem cells and CNS neurons.Neuron 46:369-372
Grande A, Sumiyoshi K, Lopez-Juarez A, Howard J, Sakthivel B, Aronow B, Campbell K, Nakafuku M, (2013) Environmental impact on direct neuronal reprogramming in vivo in the adult brain.Nat Commun 4:2373
Gueroussov S, Gonatopoulos-Pournatzis T, Irimia M, Raj B, Lin ZY, Gingras AC, Blencowe BJ, (2015) An alternative splicing event amplifies evolutionary differences between vertebrates.Science 349:868-873
Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G, (2014) In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model.Cell Stem Cell 14:188-202
Hamilton BJ, Genin A, Cron RQ, Rigby WF, (2003) Delineation of a novel pathway that regulates CD154 (CD40 ligand) expression.Mol Cell Biol 23:510-525
He L, Li Y, Li Y, Pu W, Huang X, Tian X, Wang Y, Zhang H, Liu Q, Zhang L, Zhao H, Tang J, Ji H, Cai D, Han Z, Han Z, Nie Y, Hu S, Wang QD, Sun R, Fei J, Wang F, Chen T, Yan Y, Huang H, Pu WT, Zhou B, (2017) Enhancing the precision of genetic lineage tracing using dual recombinases.Nat Med 23:1488-1498
Hu W, Qiu B, Guan W, Wang Q, Wang M, Li W, Gao L, Shen L, Huang Y, Xie G, Zhao H, Jin Y, Tang B, Yu Y, Zhao J, Pei G, (2015) Direct conversion of normal and Alzheimer’s disease human fibroblasts into neuronal cells by small molecules.Cell Stem Cell 17:204-212
Izquierdo JM, Majos N, Bonnal S, Martinez C, Castelo R, Guigo R, Bilbao D, Valcarcel J, (2005) Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition.Mol Cell 19:475-484
Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL, (2013) The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer.Redox Biol 1:45-49
Knoch KP, Bergert H, Borgonovo B, Saeger HD, Altkruger A, Verkade P, Solimena M, (2004) Polypyrimidine tract-binding protein promotes insulin secretory granule biogenesis.Nat Cell Biol 6:207-214
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann Y, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blöcker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowki J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, Chen YJ, Szustakowki J, (2001) Initial sequencing and analysis of the human genome.Nature 409:860-921
Li Q, Zheng S, Han A, Lin CH, Stoilov P, Fu XD, Black DL, (2014) The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation.Elife 3:e01201
Li X, Zuo X, Jing J, Ma Y, Wang J, Liu D, Zhu J, Du X, Xiong L, Du Y, Xu J, Xiao X, Wang J, Chai Z, Zhao Y, Deng H, (2015) Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons.Cell Stem Cell 17:195-203
Licatalosi DD, Yano M, Fak JJ, Mele A, Grabinski SE, Zhang C, Darnell RB, (2012) Ptbp2 represses adult-specific splicing to regulate the generation of neuronal precursors in the embryonic brain.Genes Dev 26:1626-1642
Lillevali K, Kulla A, Ord T, (2001) Comparative expression analysis of the genes encoding polypyrimidine tract binding protein (PTB) and its neural homologue (brPTB) in prenatal and postnatal mouse brain.Mech Dev 101:217-220
Lin CH, Patton JG, (1995) Regulation of alternative 3′ splice site selection by constitutive splicing factors.RNA 1:234-245
Linares AJ, Lin CH, Damianov A, Adams KL, Novitch BG, Black DL, (2015) The splicing regulator PTBP1 controls the activity of the transcription factor Pbx1 during neuronal differentiation.eLife 4:e09268
Liu Y, Miao Q, Yuan J, Han S, Zhang P, Li S, Rao Z, Zhao W, Ye Q, Geng J, Zhang X, Cheng L, (2015) Ascl1 converts dorsal midbrain astrocytes into functional neurons in vivo.J Neurosci 35:9336-9355
Liu Z, Wang L, Welch JD, Ma H, Zhou Y, Vaseghi HR, Yu S, Wall JB, Alimohamadi S, Zheng M, Yin C, Shen W, Prins JF, Liu J, Qian L, (2017) Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte.Nature 551:100-104
Llorian M, Schwartz S, Clark TA, Hollander D, Tan LY, Spellman R, Gordon A, Schweitzer AC, de la Grange P, Ast G, Smith CW, (2010) Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB.Nat Struct Mol Biol 17:1114-1123
Makeyev EV, Zhang J, Carrasco MA, Maniatis T, (2007) The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing.Mol Cell 27:435-448
Mathupala SP, (2009) Delivery of small-interfering RNA (siRNA) to the brain.Expert Opin Ther Pat 19:137-140
Mitchell SA, Spriggs KA, Bushell M, Evans JR, Stoneley M, Le Quesne JP, Spriggs RV, Willis AE, (2005) Identification of a motif that mediates polypyrimidine tract-binding protein-dependent internal ribosome entry.Genes Dev 19:1556-1571
Moreira A, Takagaki Y, Brackenridge S, Wollerton M, Manley JL, Proudfoot NJ, (1998) The upstream sequence element of the C2 complement poly(A) signal activates mRNA 3′ end formation by two distinct mechanisms.Genes Dev 12:2522-2534
Niu W, Zang T, Zou Y, Fang S, Smith DK, Bachoo R, Zhang CL, (2013) In vivo reprogramming of astrocytes to neuroblasts in the adult brain.Nat Cell Biol 15:1164-1175
Oberstrass FC, Auweter SD, Erat M, Hargous Y, Henning A, Wenter P, Reymond L, Amir-Ahmady B, Pitsch S, Black DL, Allain FH, (2005) Structure of PTB bound to RNA: specific binding and implications for splicing regulation.Science 309:2054-2057
Patton JG, Mayer SA, Tempst P, Nadal-Ginard B, (1991) Characterization and molecular cloning of polypyrimidine tract-binding protein: a component of a complex necessary for pre-mRNA splicing.Genes Dev 5:1237-1251
Pautz A, Linker K, Hubrich T, Korhonen R, Altenhofer S, Kleinert H, (2006) The polypyrimidine tract-binding protein (PTB) is involved in the post-transcriptional regulation of human inducible nitric oxide synthase expression.J Biol Chem 281:32294-32302
Polydorides AD, Okano HJ, Yang YY, Stefani G, Darnell RB, (2000) A brain-enriched polypyrimidine tract-binding protein antagonizes the ability of Nova to regulate neuron-specific alternative splicing.Proc Natl Acad Sci USA 97:6350-6355
Schoch KM, Miller TM, (2017) Antisense oligonucleotides: translation from mouse models to human neurodegenerative diseases.Neuron 94:1056-1070
Sharma S, Falick AM, Black DL, (2005) Polypyrimidine tract binding protein blocks the 5′ splice site-dependent assembly of U2AF and the prespliceosomal E complex.Mol Cell 19:485-496
Shibasaki T, Tokunaga A, Sakamoto R, Sagara H, Noguchi S, Sasaoka T, Yoshida N, (2013) PTB deficiency causes the loss of adherens junctions in the dorsal telencephalon and leads to lethal hydrocephalus.Cereb Cortex 23:1824-1835
Singh R, Valcarcel J, Green MR, (1995) Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins.Science 268:1173-1176
Singh SK, Kagalwala MN, Parker-Thornburg J, Adams H, Majumder S, (2008) REST maintains self-renewal and pluripotency of embryonic stem cells.Nature 453:223-227
Spellman R, Smith CW, (2006) Novel modes of splicing repression by PTB.Trends Biochem Sci 31:73-76
Spellman R, Llorian M, Smith CW, (2007) Crossregulation and functional redundancy between the splicing regulator PTB and its paralogs nPTB and ROD1.Mol Cell 27:420-434
Su Z, Niu W, Liu ML, Zou Y, Zhang CL, (2014) In vivo conversion of astrocytes to neurons in the injured adult spinal cord.Nat Commun 5:3338
Torper O, Pfisterer U, Wolf DA, Pereira M, Lau S, Jakobsson J, Bjorklund A, Grealish S, Parmar M, (2013) Generation of induced neurons via direct conversion in vivo.Proc Natl Acad Sci USA 110:7038-7043
Vierbuchen T, Wernig M, (2012) Molecular roadblocks for cellular reprogramming.Mol Cell 47:827-838
Vuong CK, Black DL, Zheng S, (2016) The neurogenetics of alternative splicing.Nat Rev Neurosci 17:265-281
Vuong JK, Lin CH, Zhang M, Chen L, Black DL, Zheng S, (2016) PTBP1 and PTBP2 serve both specific and redundant functions in neuronal Pre-mRNA splicing.Cell Rep 17:2766-2775
Wang J, Pederson T, (1990) A 62,000 molecular weight spliceosome protein crosslinks to the intron polypyrimidine tract.Nucleic Acids Res 18:5995-6001
Whitman SA, Long M, Wondrak GT, Zheng H, Zhang DD, (2013) Nrf2 modulates contractile and metabolic properties of skeletal muscle in streptozotocin-induced diabetic atrophy.Exp Cell Res 319:2673-2683
Wollerton MC, Gooding C, Wagner EJ, Garcia-Blanco MA, Smith CW, (2004) Autoregulation of polypyrimidine tract binding protein by alternative splicing leading to nonsense-mediated decay.Mol Cell 13:91-100
Xue Y, Zhou Y, Wu T, Zhu T, Ji X, Kwon YS, Zhang C, Yeo G, Black DL, Sun H, Fu XD, Zhang Y, (2009) Genome-wide analysis of PTB-RNA interactions reveals a strategy used by the general splicing repressor to modulate exon inclusion or skipping.Mol Cell 36:996-1006
Xue Y, Ouyang K, Huang J, Zhou Y, Ouyang H, Li H, Wang G, Wu Q, Wei C, Bi Y, Jiang L, Cai Z, Sun H, Zhang K, Zhang Y, Chen J, Fu XD, (2013) Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated microRNA circuits.Cell 152:82-96
Xue Y, Qian H, Hu J, Zhou B, Zhou Y, Hu X, Karakhanyan A, Pang Z, Fu XD, (2016) Sequential regulatory loops as key gatekeepers for neuronal reprogramming in human cells.Nat Neurosci 19:807-815
Yamamoto H, Tsukahara K, Kanaoka Y, Jinno S, Okayama H, (1999) Isolation of a mammalian homologue of a fission yeast differentiation regulator.Mol Cell Biol 19:3829-3841
Yeo M, Lee SK, Lee B, Ruiz EC, Pfaff SL, Gill GN, (2005) Small CTD phosphatases function in silencing neuronal gene expression.Science 307:596-600
Yoo AS, Sun AX, Li L, Shcheglovitov A, Portmann T, Li Y, Lee-Messer C, Dolmetsch RE, Tsien RW, Crabtree GR, (2011) MicroRNA-mediated conversion of human fibroblasts to neurons.Nature 476:228-231
Zheng S, Gray EE, Chawla G, Porse BT, O’Dell TJ, Black DL, (2012) PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2.Nat Neurosci 15(381–388):S381
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