title: Progressive impairment of muscle regeneration in muscleblind-like 3 isoform knockout mice.
abstract: The muscleblind-like (MBNL) genes encode alternative splicing factors that are essential for the postnatal development of multiple tissues, and the inhibition of MBNL activity by toxic C(C)UG repeat RNAs is a major pathogenic feature of the neuromuscular disease myotonic dystrophy. While MBNL1 controls fetal-to-adult splicing transitions in muscle and MBNL2 serves a similar role in the brain, the function of MBNL3 in vivo is unknown. Here, we report that mouse Mbnl3, which encodes protein isoforms that differ in the number of tandem zinc-finger RNA-binding motifs and subcellular localization, is expressed primarily during embryonic development but also transiently during injury-induced adult skeletal muscle regeneration. Mbnl3 expression is required for normal C2C12 myogenic differentiation and high-throughput sequencing combined with cross-linking/immunoprecipitation analysis indicates that Mbnl3 binds preferentially to the 3' untranslated regions of genes implicated in cell growth and proliferation. In addition, Mbnl3ΔE2 isoform knockout mice, which fail to express the major Mbnl3 nuclear isoform, show age-dependent delays in injury-induced muscle regeneration and impaired muscle function. These results suggest that Mbnl3 inhibition by toxic RNA expression may be a contributing factor to the progressive skeletal muscle weakness and wasting characteristic of myotonic dystrophy.
authors: Department of Molecular Genetics and Microbiology, Genetics Institute and the Center for NeuroGenetics, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors: Michael G
authors: MG
authors: Poulos
authors: Ranjan
authors: R
authors: Batra
authors: Moyi
authors: M
authors: Li
authors: Yuan
authors: Y
authors: Yuan
authors: Chaolin
authors: C
authors: Zhang
authors: Robert B
authors: RB
authors: Darnell
authors: Maurice S
authors: MS
authors: Swanson
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins; D012038:Regeneration / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D002352:Carrier Proteins; C522920:MBNL3 protein, mouse; D016601:RNA-Binding Proteins
references: J Mol Biol. 2011 Jan 28;405(4):1004-26
references: 21110983
references: J Biol Chem. 2010 Oct 29;285(44):33779-87
references: 20709755
references: Nature. 2009 Jul 23;460(7254):479-86
references: 19536157
references: Acta Neuropathol. 2007 Nov;114(5):527-35
references: 17661063
references: EMBO J. 2006 Sep 20;25(18):4271-83
references: 16946708
references: Nat Biotechnol. 2011 Jun 01;29(7):607-14
references: 21633356
references: EMBO J. 2000 Sep 1;19(17):4439-48
references: 10970838
references: EMBO J. 2004 Aug 4;23(15):3103-12
references: 15257297
references: Nat Struct Mol Biol. 2010 Feb;17(2):187-93
references: 20098426
references: Neuron. 2012 Aug 9;75(3):437-50
references: 22884328
references: Histopathology. 2011 Dec;59(6):1215-28
references: 22175901
references: Differentiation. 2008 Mar;76(3):299-309
references: 17697127
references: Cell Mol Life Sci. 2013 Jun;70(12):2031-44
references: 22968342
references: Mol Cell. 2002 Jul;10(1):35-44
references: 12150905
references: Hum Mol Genet. 2002 Apr 1;11(7):805-14
references: 11929853
references: Structure. 2012 Apr 4;20(4):654-66
references: 22483112
references: PLoS One. 2008 Aug 06;3(8):e2880
references: 18682727
references: Nature. 1977 Dec 22-29;270(5639):725-7
references: 563524
references: Biochem Biophys Res Commun. 2007 Sep 14;361(1):151-5
references: 17644069
references: Int J Biochem Cell Biol. 2008;40(10):2303-14
references: 18490187
references: Cold Spring Harb Perspect Biol. 2011 Jan 01;3(1):a000778
references: 21084389
references: Aging Cell. 2007 Jun;6(3):371-82
references: 17381551
references: Hum Mol Genet. 2009 Apr 15;18(8):1471-81
references: 19223393
references: Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):266-86
references: 21935890
references: Nucleic Acids Res. 1996 Nov 15;24(22):4407-14
references: 8948631
references: Nat Cell Biol. 2005 Dec;7(12):1240-7
references: 16273094
references: Annu Rev Neurosci. 2006;29:259-77
references: 16776586
references: Cell. 2011 Jan 7;144(1):16-26
references: 21215366
references: Nucleic Acids Res. 1999 Sep 1;27(17):3534-42
references: 10446244
references: Mol Cell Biol. 2012 Oct;32(20):4155-67
references: 22890842
references: Cell. 2009 Feb 20;136(4):777-93
references: 19239895
references: Hum Mol Genet. 2004 Mar 1;13(5):495-507
references: 14722159
references: Science. 2003 Dec 12;302(5652):1978-80
references: 14671308
references: Dev Biol. 2002 Oct 1;250(1):218-30
references: 12297108
references: J Biol Chem. 2009 Mar 20;284(12):7419-23
references: 18957432
references: Gene Expr Patterns. 2003 Aug;3(4):459-62
references: 12915312
references: Nucleic Acids Res. 2010 Apr;38(7):2467-84
references: 20071745
references: Nucleic Acids Res. 2007;35(16):5474-86
references: 17702765
references: Genes Dev. 1992 Oct;6(10):1927-39
references: 1398070
references: J Biol Chem. 1991 Aug 25;266(24):15917-23
references: 1651927
references: Nucleic Acids Res. 2012 Apr;40(7):3159-71
references: 22156369
references: J Cell Biol. 2012 Mar 19;196(6):699-712
references: 22431750
references: Mol Cell. 2002 Jul;10(1):45-53
references: 12150906
references: Science. 2003 Nov 28;302(5650):1575-7
references: 14645852
references: Cell. 2012 Aug 17;150(4):710-24
references: 22901804
references: Nat Struct Mol Biol. 2008 Dec;15(12):1343-51
references: 19043415
references: J Cell Biol. 2011 Jan 10;192(1):69-81
references: 21200031
references: Front Neurosci. 2012 Oct 02;6:144
references: 23060744
references: Science. 1998 May 1;280(5364):737-41
references: 9563950
references: Nucleic Acids Res. 2009 Jul;37(Web Server issue):W202-8
references: 19458158
references: Dis Model Mech. 2013 Jan;6(1):197-205
references: 22917925
references: Methods Mol Biol. 2008;488:85-98
references: 18982285
references: Nucleic Acids Res. 2011 Apr;39(7):2769-80
references: 21109529