TY - JOUR
T1 - MeCP2 expression and function during brain development
T2 - Implications for Rett syndrome's pathogenesis and clinical evolution
AU - Kaufmann, Walter E.
AU - Johnston, Michael V.
AU - Blue, Mary E.
N1 - Funding Information:
This study was supported by NIH grants HD24448 and HD24061 and an award from the International Rett Syndrome Association to W.E.K. The authors thank Judy Wang and Pia Stanard for editorial assistance, Dr. Sakkubai Naidu and her team for their continuous support of our research, and the families involved in the Pathogenesis of Rett Syndrome Project at the Kennedy Krieger Institute for their generous participation.
PY - 2005/11
Y1 - 2005/11
N2 - Most cases of Rett syndrome (RTT) are associated with mutations of the transcriptional regulator MeCP2. On the basis of molecular structure, ontogeny, and subcellular and regional distribution, MeCP2 appears to be a link between synaptic activity and neuronal transcription. Integrating data on MeCP2 neurobiology, RTT neurobiology, MeCP2 mutational patterns in RTT and other disorders, histone profiles of relevance to RTT, and genotype-phenotype correlations in RTT, we update here our synaptic hypothesis of RTT. We postulate that MeCP2 dysfunction leads to abnormal brain development through maladjustment of neuronal gene expression to synaptic and other extra-cellular signals, mainly during the critical period of synaptic maturation. RTT phenotype will develop, only if severe MeCP2 dysfunction is present during early neuronal differentiation. Two models are proposed for explaining general and regional neuronal abnormalities in RTT and the phenotypical outcome of MeCP2 dysfunction, respectively.
AB - Most cases of Rett syndrome (RTT) are associated with mutations of the transcriptional regulator MeCP2. On the basis of molecular structure, ontogeny, and subcellular and regional distribution, MeCP2 appears to be a link between synaptic activity and neuronal transcription. Integrating data on MeCP2 neurobiology, RTT neurobiology, MeCP2 mutational patterns in RTT and other disorders, histone profiles of relevance to RTT, and genotype-phenotype correlations in RTT, we update here our synaptic hypothesis of RTT. We postulate that MeCP2 dysfunction leads to abnormal brain development through maladjustment of neuronal gene expression to synaptic and other extra-cellular signals, mainly during the critical period of synaptic maturation. RTT phenotype will develop, only if severe MeCP2 dysfunction is present during early neuronal differentiation. Two models are proposed for explaining general and regional neuronal abnormalities in RTT and the phenotypical outcome of MeCP2 dysfunction, respectively.
KW - MeCP2
KW - Phenotype
KW - Plasticity
KW - Rett syndrome
KW - Synapse
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U2 - 10.1016/j.braindev.2004.10.008
DO - 10.1016/j.braindev.2004.10.008
M3 - Article
C2 - 16182491
AN - SCOPUS:27144448737
SN - 0387-7604
VL - 27
SP - S77-S87
JO - Brain and Development
JF - Brain and Development
IS - SUPPL. 1
ER -