Can we relate MeCP2 deficiency to the structural and chemical abnormalities in the Rett brain?

      Abstract

      The mutated gene for Rett syndrome, MECP2, has now been identified in ninety percent of cases. Molecular biologists are immersed in the study of this gene's biology determining how its mutation could be responsible for such an enigmatic phenotype. In this paper the same question is considered, reexamining the structural phenotype of the Rett brain and asking; is MeCP2 present at the appropriate time and place in brain development to influence the structural and chemical abnormalities which characterize the Rett brain? Data from the literature and previous research suggest that MeCP2 is expressed during critical periods of brain development at several sites and in different neurons. It supports the idea that inadequate functioning of MeCP2 alters trophic factors and raises the possibility that replacement of these factors might improve brain function. The availability of mouse models now makes it possible to test such ideas.

      Keywords

      To read this article in full you will need to make a payment
      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Amir R.E.
        • Van Den Veyver I.
        • Wan M.
        • Tran C.Q.
        • Francke U.
        • Zoghbi H.Y.
        Rett's syndrome is caused by mutations in X-linked MECP2 encoding methyl-CpG-binding protein.
        Nat Genet. 1999; 23: 185-188
        • Shahbazian M.D.
        • Zoghbi H.Y.
        Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations.
        Curr Opin Neurol. 2001; 14: 171-176
        • Chen R.Z.
        • Akbarian S.
        • Tudor M.
        • Jaenisch R.
        Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett—like phenotype in mice.
        Nat Genet. 2001; 27: 327-331
        • Guy J.
        • Hendrich B.
        • Martin J.E.
        • Bird A.
        A mouse Mecp2-null mutation causes neurologic symptoms that mimic Rett syndrome.
        Nat Genet. 2001; 27: 322-326
        • Shahbazian M.D.
        • Antalffy B.
        • Armstrong D.L.
        • Zoghbi H.Y.
        Insight into Rett sydnrone:MeCP2 levels display tissue and cell specific differences and correlate with neuronal maturation.
        Hum Mol Genet. 2002; 11: 115-124
        • Lasalle J.M.
        • Goldstine J.
        • Balmer D.
        • Greco Ch.
        Quantitative localization of heterogeneous methyo-CpG-binding protein-2 (MeCP2) expression phenotypes in normal and Rett Syndrome brain by laser and scanning cytometry.
        Hum Mol Genet. 2001; 10: 1729-1740
        • Ronnett G.V.
        • Leopold D.
        • Cai X.
        • Hoffbuhr K.C.
        • Moses L.
        • Hoffman E.P.
        • et al.
        Olfactory biopsies demonstrate a defect in neuronal development in Rett's syndrome.
        Ann Neurol. 2003; 54: 206-218
        • Chen W.G.
        • Chang Q.
        • Lin Y.L.
        • Meissner A.
        • West A.E.
        • Griffith E.C.
        • et al.
        Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2.
        Science. 2003; 31: 885-889
        • Armstrong D.D.
        • Kinney H.C.
        The neuropathology of the Rett disorder.
        in: Kerr A. Witt Engerstrom I. Rett disorder and the developing brain. Oxford Press, Oxford2001: 57-84
        • Casanova M.F.
        • Buxhoeveden D.
        • Switala A.
        • Roy E.
        Rett syndrome as a minicolumnopathy.
        Clin Neuropathol. 2003; 22: 163-168
        • Armstrong D.
        • Dunn K.
        • Antalffy B.
        • Trivedi R.
        Selective dendritic alterations in the cortex of Rett syndrome.
        J Neuropathol Exp Neurol. 1995; 54: 195-201
        • Armstrong D.D.
        • Dunn K.
        • Antalffy B.
        Decreased dendritic branching in frontal, motor, limbic cortex in Rett syndrome compared with trisomy 21.
        J Neuropathol Exp Neurol. 1998; 57: 1013-1017
        • Belichenko P.V.
        • Oldfors A.
        • Hagberg B.
        • Dahlstrom A.S.
        Rett syndrome: 3-D confocal microscopy of cortical pyramidal dendrites and afferents.
        Neurol Rep. 1994; 5: 1509-1513
        • Belichenko P.V.
        • Dahlstrom A.
        Studies on the 3-dimentional architecture of dendritic spines and varicosities in human cortex by confocal laser scanning microscopy and Lucifer Yellow microinjections.
        J Neurosci Methods. 1995; 57: 55-61
        • Kaufmann W.E.
        • Naidu S.
        • Budden S.
        Abnormal expression of microtubule-associated protein 2 (MAP2) in the neocortex in Rett syndrome.
        Neuropediatrics. 1995; 26: 109-113
        • Kaufmann W.E.
        • Worley P.F.
        • Taylor C.V.
        • Bremer M.
        • Isakson P.C.
        Cyclooxygenase-2 expression during rat neocortical development and in Rett syndrome.
        Brain Dev. 1997; 19: 25-34
        • Wenk G.
        Selective changes in Rett syndrome neurochemistry: findings of normal dopaminergic and decreased cholinergic function.
        Eur Child Adolesc Psychiatry. 1997; 1: 87-88
        • Lappalainen R.
        • Riikonen R.
        High levels of cerebrospinal glutamate in the Rett syndrome.
        Pediatr Neurol. 1996; 15: 213-216
        • Riikonen K.
        Neurotrophic factors in the pathogenesis in Rett Syndrome.
        J Child Neurol. 2003; 18: 693-697
        • Blue M.E.
        • Naidu S.
        • Johnston M.V.
        Development of amino acid receptors in frontal cortex from girls with Rett syndrome.
        Ann Neurol. 1999; 45: 541-545
        • Brucke T.
        • Sofic E.
        • Killian W.
        • Rett A.
        • Riederer P.
        Reduced concentrations and increased metabolism of biogenic amines in a single case of Rett syndrome: a post mortem brain study.
        J Neurol Transm. 1987; 68: 315-324
        • Wenk G.L.
        • Hauss-Wegrzyniak B.
        Altered cholinergic function in the basal forebrain of girls with Rett syndrome.
        Neuropediatrics. 1999; 30: 125-129
        • Lappalainen R.
        • Lindholm D.
        • Riikonen R.
        Low levels of nerve growth factor in cerebrospinal fluid of children with Rett syndrome.
        J Child Neurol. 1996; 11: 296-300
        • Matsuishi T.
        • Nagamitsu S.
        • Yamashita Y.
        • Murakami Y.
        • Kimura A.
        • Sakai T.
        • et al.
        Decreased cerebrospinal levels of substance P in patients with Rett syndrome.
        Ann Neurol. 1997; 42: 978-981
        • Lekman A.
        • Witt Engerstrom I.
        • Holmber B.
        • Percy A.K.
        • Svennerholm L.
        • Hagberg B.
        CSF and urine biogenic amine metabolites in Rett syndrome.
        Clin Genet. 1990; 37: 173-178
        • Nielsen J.B.
        • Bertelson Z.A.
        • Lou H.C.
        Low CSF HVA levels in Rett Syndrome: a reflection of restricted synapse formation?.
        Brain Dev. 1992; 14: S63-S65
        • Perry T.I.
        • Dunn H.G.
        • Ho H.H.
        • Crichton J.U.
        Cerebrospinal fluid values for monoamine metabolites, gamma-amino butyric acid and other amino acid compounds in Rett syndrome.
        J Pediatr. 1988; 112: 234-238
        • Zoghbi H.Y.
        • Milstien S.
        • Butler I.J.
        • Smith O.B.
        • Kaufmann S.
        • Glaze D.G.
        • Percy A.K.
        Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome.
        Ann Neurol. 1989; 25: 56-60
      1. Bauman MI, Kemper MD, Arin DM. Pervasive neuroanatomic abnormalities of the brain in three cases of Rett's syndrome. 1995;45:1581–6.

        • Kitt C.A.
        • Wilcox B.J.
        Preliminary evidence for neurodegenerative changes in the substantia nigra in Rett syndrome.
        Neuropediatrics. 1995; 25: 114-118
        • Ringstedt T.
        • Linnarsson S.
        • Wagner J.
        • Lendahl U.
        • Kokaia Z.
        • Arenas E.
        • et al.
        BDNF regulates reelin expression and Cajal–Retzius cell development in the cerebral cortex.
        Neuron. 1998; 21: 3205-3315
        • Sundstrom E.
        • Kolare S.
        • Souverbie F.
        • Samuelson E.B.
        • Pscjera H.
        • Lunell N.O.
        • et al.
        Neurochemical differentiation of human bulbospinal monoaminergic neurons during the first trimester.
        Brain Res Dev Brain Res. 1993; 7: 1-12
        • Armstrong D.D.
        • Deguchi K.
        • Antalffy B.
        Survey of MeCp2 in the Rett syndrome and the non-Rett syndrome brain.
        J Chid Neurol. 2003; 18: 683-687