title: Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene.
abstract: Spinal muscular atrophy (SMA) is a common (approximately 1:6400) autosomal recessive neuromuscular disorder caused by a paucity of the survival of motor neuron (SMN) protein. Although widely recognized to cause selective spinal motor neuron loss when deficient, the precise cellular site of action of the SMN protein in SMA remains unclear. In this study we sought to determine the consequences of selectively depleting SMN in the motor neurons of model mice. Depleting but not abolishing the protein in motor neuronal progenitors causes an SMA-like phenotype. Neuromuscular weakness in the model mice is accompanied by peripheral as well as central synaptic defects, electrophysiological abnormalities of the neuromuscular junctions, muscle atrophy, and motor neuron degeneration. However, the disease phenotype is more modest than that observed in mice expressing ubiquitously low levels of the SMN protein, and both symptoms as well as early electrophysiological abnormalities that are readily apparent in neonates were attenuated in an age-dependent manner. We conclude that selective knock-down of SMN in motor neurons is sufficient but may not be necessary to cause a disease phenotype and that targeting these cells will be a requirement of any effective therapeutic strategy. This realization is tempered by the relatively mild SMA phenotype in our model mice, one explanation for which is the presence of normal SMN levels in non-neuronal tissue that serves to modulate disease severity.
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Gyu-Hwan
authors.initials: GH
authors.lastname: Park
authors.forename: Yuka
authors.initials: Y
authors.lastname: Maeno-Hikichi
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Awano
authors.forename: Lynn T
authors.initials: LT
authors.lastname: Landmesser
authors.forename: Umrao R
authors.initials: UR
authors.lastname: Monani
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D004576:Electromyography / Q000379:methods; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D007537:Isometric Contraction / Q000502:physiology; D053208:Kaplan-Meier Estimate; D008164:Luminescent Proteins / Q000235:genetics; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D055369:Miniature Postsynaptic Potentials / Q000235:genetics; D009043:Motor Activity / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009469:Neuromuscular Junction / Q000473:pathology; D000076104:Oligodendrocyte Transcription Factor 2; D018408:Patch-Clamp Techniques; D011950:Receptors, Cholinergic / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000473:pathology / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002795:Choline O-Acetyltransferase; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D011950:Receptors, Cholinergic; D055540:Survival of Motor Neuron 2 Protein; C405708:OLIG2 protein, human; C526477:SMN2 protein, human
references.citation: Science. 2009 Nov 20;326(5956):1127-30
references.pmid: 19965435
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9920-5
references.pmid: 9275227
references.citation: Hum Mol Genet. 2008 Aug 15;17(16):2552-69
references.pmid: 18492800
references.citation: Cell. 1995 Jan 13;80(1):155-65
references.pmid: 7813012
references.citation: Synapse. 2003 Nov;50(2):117-29
references.pmid: 12923814
references.citation: J Cell Biol. 2007 Oct 8;179(1):139-49
references.pmid: 17923533
references.citation: PLoS One. 2008 Sep 15;3(9):e3209
references.pmid: 18791638
references.citation: J Neurosci. 1993 Feb;13(2):834-55
references.pmid: 8426240
references.citation: Genesis. 2006 Mar;44(3):130-5
references.pmid: 16496331
references.citation: J Clin Invest. 2010 Apr;120(4):1253-64
references.pmid: 20234094
references.citation: Cell. 2000 May 26;101(5):485-98
references.pmid: 10850491
references.citation: Proc Natl Acad Sci U S A. 1999 May 25;96(11):6307-11
references.pmid: 10339583
references.citation: Neuron. 1997 Dec;19(6):1237-48
references.pmid: 9427247
references.citation: J Cell Biol. 2003 Nov 24;163(4):801-12
references.pmid: 14623865
references.citation: Nat Genet. 2003 Aug;34(4):460-3
references.pmid: 12833158
references.citation: PLoS One. 2007 Sep 26;2(9):e921
references.pmid: 17895963
references.citation: Sci Transl Med. 2010 Jun 9;2(35):35ra42
references.pmid: 20538619
references.citation: Science. 1997 Jan 17;275(5298):356-61
references.pmid: 8994026
references.citation: Nature. 1998 Mar 5;392(6671):82-6
references.pmid: 9510251
references.citation: Nature. 2009 Jun 11;459(7248):842-6
references.pmid: 19421194
references.citation: Am J Pathol. 2004 Nov;165(5):1731-41
references.pmid: 15509541
references.citation: J Neurosci. 2009 Jan 21;29(3):842-51
references.pmid: 19158308
references.citation: Nat Genet. 2002 Apr;30(4):377-84
references.pmid: 11925564
references.citation: Neuron. 2001 Sep 13;31(5):773-89
references.pmid: 11567616
references.citation: Hum Mol Genet. 1999 Jul;8(7):1177-83
references.pmid: 10369862
references.citation: Nucleic Acids Res. 1999 Oct 1;27(19):e27
references.pmid: 10481039
references.citation: Neuron. 2009 Feb 26;61(4):556-69
references.pmid: 19249276
references.citation: Annu Rev Physiol. 2001;63:847-69
references.pmid: 11181978
references.citation: J Neurosci. 2000 Sep 1;20(17):6529-39
references.pmid: 10964958
references.citation: J Neurosci. 2010 Jan 20;30(3):849-57
references.pmid: 20089893
references.citation: J Neurosci. 2006 Aug 30;26(35):8983-7
references.pmid: 16943554
references.citation: Neurobiol Dis. 2007 Aug;27(2):207-19
references.pmid: 17561409
references.citation: Hum Mol Genet. 2000 Feb 12;9(3):333-9
references.pmid: 10655541
references.citation: Curr Neurol Neurosci Rep. 2010 Mar;10(2):108-17
references.pmid: 20425235
references.citation: J Cell Biol. 2003 Jan 6;160(1):41-52
references.pmid: 12515823
references.citation: J Physiol. 1980 Feb;299:621-38
references.pmid: 6103954
references.citation: J Child Neurol. 2007 Aug;22(8):979-89
references.pmid: 17761653
references.citation: Prog Neurobiol. 2001 Jul;64(4):393-429
references.pmid: 11275359
references.citation: Hum Mol Genet. 2008 Apr 15;17(8):1063-75
references.pmid: 18178576
references.citation: Neuron. 2005 Dec 22;48(6):885-96
references.pmid: 16364894
references.citation: Cell. 1997 Sep 19;90(6):1023-9
references.pmid: 9323130
references.citation: Mol Cell Neurosci. 2009 Sep;42(1):66-74
references.pmid: 19497369
references.citation: Hum Mol Genet. 2008 Sep 15;17(18):2900-9
references.pmid: 18603534
references.citation: Neuron. 2000 Feb;25(2):331-43
references.pmid: 10719889
references.citation: Nat Biotechnol. 2010 Mar;28(3):271-4
references.pmid: 20190738
references.citation: BMC Dev Biol. 2001;1:4
references.pmid: 11299042
references.citation: J Neurosci. 2005 Jan 12;25(2):343-51
references.pmid: 15647477
references.citation: Cell. 1997 Sep 19;90(6):1013-21
references.pmid: 9323129
references.citation: Hum Mol Genet. 2005 Mar 15;14(6):845-57
references.pmid: 15703193
references.citation: J Cell Biol. 2001 Mar 5;152(5):1107-14
references.pmid: 11238465
references.citation: Genesis. 2000 Feb;26(2):127-9
references.pmid: 10686606
references.citation: Hum Mol Genet. 2000 Mar 22;9(5):849-58
references.pmid: 10749994
references.citation: Nature. 2007 Nov 29;450(7170):717-20
references.pmid: 18046410