title: Neuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation.
abstract: Rett Syndrome (RTT), a progressive neurological disorder characterized by developmental regression and loss of motor and language skills, is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Neurostructural phenotypes including decreased neuronal size, dendritic complexity, and spine density have been reported in postmortem RTT brain tissue and in Mecp2 animal models. How these changes in neuronal morphology are related to RTT-like phenotype and MeCP2 function, and the extent to which restoration of neuronal morphology can be used as a cellular readout in therapeutic studies, however, remain unclear. Here, we systematically examined neuronal morphology in vivo across three Mecp2 mouse models representing Mecp2 loss-of-function, partial loss-of-function, and gain-of-function mutations, at developmental time points corresponding to early- and late-symptomatic RTT-like behavioral phenotypes. We found that in Mecp2 loss-of-function mouse models, dendritic complexity is reduced in a mild, age-dependent, and brain region-specific manner, whereas soma size is reduced consistently throughout development. Neither phenotype, however, is altered in Mecp2 gain-of-function mice. Our results suggest that, in the cell types we examined, the use of dendritic morphology as a cellular readout of RTT phenotype and therapeutic efficacy should be cautioned, as it is intrinsically variable. In contrast, soma size may be a robust and reliable marker for evaluation of MeCP2 function in Mecp2 loss-of-function studies.
authors: Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: I-Ting J
authors: IT
authors: Wang
authors: Arith-Ruth S
authors: AR
authors: Reyes
authors: Zhaolan
authors: Z
authors: Zhou
mesh_terms: D000375:Aging / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology*; D003712:Dendrites / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000473:pathology*; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D049452:Green Fluorescent Proteins
keywords: Dendritic branching; MECP2; Mouse model; Neuronal morphology; Rett syndrome; Soma size
references: BMC Neurosci. 2010 Feb 17;11:19
references: 20163734
references: Nat Genet. 2012 Jan 08;44(2):206-11
references: 22231481
references: PLoS One. 2012;7(3):e33153
references: 22427975
references: Brain. 2006 Apr;129(Pt 4):887-98
references: 16467389
references: J Comp Neurol. 2008 May 1;508(1):184-95
references: 18306326
references: Hum Mol Genet. 2004 Nov 1;13(21):2679-89
references: 15351775
references: Nat Rev Genet. 2006 Jun;7(6):415-26
references: 16708070
references: Nat Genet. 1999 Oct;23(2):185-8
references: 10508514
references: Neurology. 1995 Aug;45(8):1581-6
references: 7644058
references: Brain. 2012 Sep;135(Pt 9):2699-710
references: 22525157
references: Nat Neurosci. 2011 Nov 27;15(2):274-83
references: 22119903
references: Nat Rev Neurosci. 2008 Mar;9(3):206-21
references: 18270515
references: Cell. 2010 Nov 12;143(4):527-39
references: 21074045
references: J Neurosci. 2012 Feb 29;32(9):3109-17
references: 22378884
references: PLoS One. 2012;7(2):e31835
references: 22363746
references: Am J Med Genet A. 2007 Feb 15;143(4):364-9
references: 17256798
references: Neuron. 2002 Jul 18;35(2):243-54
references: 12160743
references: Neurobiol Dis. 2007 Jul;27(1):77-89
references: 17532643
references: Neurobiol Dis. 2009 Apr;34(1):71-7
references: 19167498
references: Neuroreport. 1994 Jul 21;5(12):1509-13
references: 7948850
references: J Comp Neurol. 2009 May 20;514(3):240-58
references: 19296534
references: Hum Mol Genet. 2003 Oct 15;12 Spec No 2:R221-7
references: 12928486
references: Neuron. 2011 Oct 6;72(1):72-85
references: 21982370
references: PLoS One. 2012;7(3):e31896
references: 22412847
references: J Neuropathol Exp Neurol. 1995 Mar;54(2):195-201
references: 7876888
references: Neural Plast. 2012;2012:976164
references: 22919518
references: J Child Neurol. 2005 Sep;20(9):747-53
references: 16225830
references: Nat Genet. 2001 Mar;27(3):322-6
references: 11242117
references: J Neuropathol Exp Neurol. 2005 Jun;64(6):537-44
references: 15977646
references: Stem Cells. 2012 Oct;30(10):2128-39
references: 22865604
references: Neuron. 2007 Nov 8;56(3):422-37
references: 17988628
references: Nature. 2011 Jun 29;475(7357):497-500
references: 21716289
references: Cereb Cortex. 2000 Oct;10(10):992-1004
references: 11007550
references: Front Biol (Beijing). 2012 Oct;7(5):428-435
references: 24999353
references: Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2029-34
references: 19208815
references: Neuroscience. 2006;139(4):1449-60
references: 16549272
references: Neuron. 2006 Oct 19;52(2):255-69
references: 17046689
references: Neurobiol Dis. 2005 Jun-Jul;19(1-2):18-27
references: 15837557
references: J Mol Med (Berl). 2011 Apr;89(4):389-98
references: 21120444
references: Neurobiol Dis. 2009 Aug;35(2):219-33
references: 19442733
references: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6033-8
references: 15069197
references: Neurobiol Dis. 2009 May;34(2):199-211
references: 19217433
references: J Neurosci. 2009 Sep 30;29(39):12187-95
references: 19793977
references: Science. 2007 Feb 23;315(5815):1143-7
references: 17289941
references: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1931-6
references: 17267601
references: Dis Model Mech. 2012 Nov;5(6):733-45
references: 23115203
references: Mol Cell Neurosci. 2004 Nov;27(3):306-21
references: 15519245
references: Neuron. 2007 Oct 4;56(1):58-65
references: 17920015
references: J Neurosci. 2006 Jan 4;26(1):319-27
references: 16399702
references: J Neurosci. 2009 Sep 9;29(36):11263-70
references: 19741133
references: Nat Genet. 2001 Mar;27(3):327-31
references: 11242118
references: Acta Neuropathol. 1988;76(2):142-58
references: 2900587
references: Ann Neurol. 2009 Dec;66(6):771-82
references: 20035514
references: Neuron. 2000 Oct;28(1):41-51
references: 11086982
references: J Anat. 1953 Oct;87(4):387-406
references: 13117757