Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140V mouse model of Rett syndrome/X-linked mental retardation

BackgroundRett syndrome (RTT), a common cause of mental retardation in girls, is associated with mutations in the MECP2 gene. Most human cases of MECP2 mutation in girls result in classical or variant forms of RTT. When these same mutations occur in males, they often present as severe neonatal encephalopathy. However, some MECP2 mutations can also lead to diseases characterized as mental retardation syndromes, particularly in boys. One of these mutations, A140V, is a common, recurring missense mutation accounting for about 0.6% of all MeCP2 mutations and ranking 21st by frequency. It has been described in familial X-linked mental retardation (XLMR), PPM- X syndrome (Parkinsonism, Pyramidal signs, Macroorchidism, X-linked mental retardation) and in other neuropsychiatric syndromes. Interestingly, this mutation has been reported to preserve the methyl-CpG binding function of the MeCP2 protein while compromising its ability to bind to the mental retardation associated protein ATRX.ResultsWe report the construction and initial characterization of a mouse model expressing the A140V MeCP2 mutation. These initial descriptive studies in male hemizygous mice have revealed brain abnormalities seen in both RTT and mental retardation. The abnormalities found include increases in cell packing density in the brain and a significant reduction in the complexity of neuronal dendritic branching. In contrast to some MeCP2 mutation mouse models, the A140V mouse has an apparently normal lifespan and normal weight gain patterns with no obvious seizures, tremors, breathing difficulties or kyphosis.ConclusionWe have identified various neurological abnormalities in this mouse model of Rett syndrome/X-linked mental retardation which may help to elucidate the manner in which MECP2 mutations cause neuronal changes resulting in mental retardation without the confounding effects of seizures, chronic hypoventilation, or other Rett syndrome associated symptoms.

[1]  D. Higgs,et al.  Loss of Atrx Affects Trophoblast Development and the Pattern of X-Inactivation in Extraembryonic Tissues , 2006, PLoS genetics.

[2]  M. Mangelsdorf,et al.  The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis. , 2005, The Journal of clinical investigation.

[3]  M. Nakao,et al.  Solution Structure of the Methyl-CpG Binding Domain of Human MBD1 in Complex with Methylated DNA , 2001, Cell.

[4]  B. Winnepenninckx,et al.  Identification of a family with nonspecific mental retardation (MRX79) with the A140V mutation in the MECP2 gene: Is there a need for routine screening? , 2002, Human mutation.

[5]  H. Moser,et al.  Dendritic anomalies in disorders associated with mental retardation. , 1999, Cerebral cortex.

[6]  A. Bird,et al.  MeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin , 1997, Cell.

[7]  Hao Wu,et al.  The Ups and Downs of BDNF in Rett Syndrome , 2006, Neuron.

[8]  E. Hoffman,et al.  Olfactory biopsies demonstrate a defect in neuronal development in Rett's syndrome , 2003, Annals of neurology.

[9]  Stephen T. C. Wong,et al.  MeCP2, a Key Contributor to Neurological Disease, Activates and Represses Transcription , 2008, Science.

[10]  H. Zoghbi,et al.  Rett Syndrome: A Prototypical Neurodevelopmental Disorder , 2004, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[11]  B. Antalffy,et al.  Decreased Dendritic Branching in Frontal, Motor and Limbic Cortex in Rett Syndrome Compared with Trisomy 21 , 1998, Journal of neuropathology and experimental neurology.

[12]  J. Coyle,et al.  Ube3a mRNA and protein expression are not decreased in Mecp2 R168X mutant mice , 2007, Brain Research.

[13]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[14]  G. Ronnett,et al.  MeCP2 deficiency disrupts axonal guidance, fasciculation, and targeting by altering Semaphorin 3F function , 2009, Molecular and Cellular Neuroscience.

[15]  N. Bérubé,et al.  Altered visual function and interneuron survival in Atrx knockout mice: inference for the human syndrome. , 2009, Human molecular genetics.

[16]  L. Firestone,et al.  Gene Knockout of the α6 Subunit of the γ-Aminobutyric Acid Type A Receptor: Lack of Effect on Responses to Ethanol, Pentobarbital, and General Anesthetics , 1997 .

[17]  G. Ronnett,et al.  The transcriptional repressor Mecp2 regulates terminal neuronal differentiation , 2004, Molecular and Cellular Neuroscience.

[18]  J. Machado-Salas.  Abnormal dendritic patterns and aberrant spine development in Bourneville's disease--a Golgi survey. , 1984, Clinical neuropathology.

[19]  S. Klauck,et al.  A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. , 2002, American journal of human genetics.

[20]  D. Higgs,et al.  Molecular-clinical spectrum of the ATR-X syndrome. , 2000, American journal of medical genetics.

[21]  A. Federico,et al.  A Rett syndrome MECP2 mutation that causes mental retardation in men , 2002, Neurology.

[22]  H. Ropers,et al.  MECP2 is highly mutated in X-linked mental retardation. , 2001, Human molecular genetics.

[23]  Sholl Da.  Dendritic organization in the neurons of the visual and motor cortices of the cat. , 1953 .

[24]  A. Federico,et al.  MECP2 mutation in male patients with non‐specific X‐linked mental retardation , 2000, FEBS letters.

[25]  T. Ichikawa,et al.  Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. , 2005, Journal of neuropathology and experimental neurology.

[26]  J. Roder,et al.  Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  G. Ronnett,et al.  Temporal and regional differences in the olfactory proteome as a consequence of MeCP2 deficiency. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Eric C. Griffith,et al.  Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation , 2006, Neuron.

[29]  D. Cohen,et al.  MECP2 mutation in a boy with language disorder and schizophrenia. , 2002, The American journal of psychiatry.

[30]  J. Chelly,et al.  Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized , 2006, Nature Reviews Genetics.

[31]  J. Fryns,et al.  A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. , 2000, American journal of human genetics.

[32]  S. Nelson,et al.  The Disease Progression of Mecp2 Mutant Mice Is Affected by the Level of BDNF Expression , 2006, Neuron.

[33]  Noriyuki Kishi,et al.  MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions , 2004, Molecular and Cellular Neuroscience.

[34]  Jean Aicardi,et al.  A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: Report of 35 cases , 1983, Annals of neurology.

[35]  G. Ronnett,et al.  MeCP2 mutation causes distinguishable phases of acute and chronic defects in synaptogenesis and maintenance, respectively , 2008, Molecular and Cellular Neuroscience.

[36]  T. Kemper,et al.  Pervasive neuroanatomic abnormalities of the brain in three cases of Rett's syndrome , 1995, Neurology.

[37]  L. Firestone,et al.  Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. , 1997, Molecular pharmacology.

[38]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[39]  BMC Neuroscience , 2003 .

[40]  D. Armstrong.  Neuropathology of Rett syndrome. , 2002, Mental retardation and developmental disabilities research reviews.

[41]  M. Nakao,et al.  Functional characterisation of MeCP2 mutations found in male patients with X linked mental retardation , 2002, Journal of medical genetics.

[42]  J. Cigudosa,et al.  The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. , 2009, Human molecular genetics.

[43]  Juan I. Young,et al.  Mice with Truncated MeCP2 Recapitulate Many Rett Syndrome Features and Display Hyperacetylation of Histone H3 , 2002, Neuron.

[44]  Christina Thaller,et al.  Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome , 2006, Proceedings of the National Academy of Sciences.

[45]  H. G. Dunn,et al.  Rett Syndrome: Review of Biological Abnormalities , 2001, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[46]  Amy Lawson-Yuena,et al.  Ube 3 a mRNA and protein expression are not decreased in Mecp 2 R 168 X mutant mice , 2007 .

[47]  B. Antalffy,et al.  Selective Dendritic Alterations in the Cortex of Rett Syndrome , 1995, Journal of neuropathology and experimental neurology.

[48]  B. Hagberg.  Rett's Syndrome: Prevalence and Impact on Progressive Severe Mental Retardation in Girls , 1985, Acta paediatrica Scandinavica.

[49]  A. Bird,et al.  DNA methylation specifies chromosomal localization of MeCP2 , 1996, Molecular and cellular biology.

[50]  Mu-ming Poo,et al.  Neurotrophins as synaptic modulators , 2001, Nature Reviews Neuroscience.

[51]  L. Villard,et al.  Alpha-thalassemia/mental retardation syndrome, X-Linked (ATR-X, MIM #301040, ATR-X/XNP/XH2 gene MIM #300032) , 2002, European Journal of Human Genetics.

[52]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[53]  A. Bird,et al.  Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation , 2007, Proceedings of the National Academy of Sciences.

[54]  A. Bird,et al.  A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome , 2001, Nature Genetics.

[55]  A. Munnich,et al.  Mutations in PHD‐like domain of the ATRX gene correlate with severe psychomotor impairment and severe urogenital abnormalities in patients with ATRX syndrome , 2006, Clinical genetics.

[56]  R. Jaenisch,et al.  Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice , 2001, Nature Genetics.

[57]  A. Munnich,et al.  MECP2 mutation in non-fatal, non-progressive encephalopathy in a male , 2001, Journal of medical genetics.

[58]  U. Francke,et al.  Comparative study of brain morphology in Mecp2 mutant mouse models of Rett syndrome , 2008, The Journal of comparative neurology.

[59]  B Hagberg,et al.  Rett syndrome: 3‐D confocal microscopy of cortical pyramidal dendrites and afferents , 1994, Neuroreport.