MeCP2 involvement in the regulation of neuronal alpha-tubulin production.
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by a dominant mutation in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Neuroanatomically, RTT is characterized by a reduction in dendritic arborization and perikaryal size in the brain. MECP2 binds methylated promoters and facilitates assembly of a multiprotein repressor complex that includes Sin3A and the histone deacetylases HDAC1/HDAC2. MeCP2 has recently been found to be downregulated in autistic spectrum disorders such as Angelman syndrome (AS) and RTT, which share some phenotypic manifestations. We have conducted expression analysis of cytoskeleton-related genes in brain tissue of RTT and AS patients. Striking examples of genes with reduced expression were TUBA1B and TUBA3 that encode the ubiquitous alpha-tubulin and the neuronal specific alpha-tubulin, respectively. In accordance with the downregulation of expression of these genes, we have observed a reduction in the level of the corresponding protein product-tyrosinated alpha-tubulin. Low levels of alpha-tubulin and deteriorated cell morphology were also observed in MeCP2(-/y) MEF cells. The effects of MeCP2 deficiency in these cells were completely reversed by introducing and expressing the human MeCP2 gene. These results imply that MeCP2 is involved in the regulation of neuronal alpha-tubulin and add molecular evidence that reversal of the effects of MeCP2 deficiency is achievable. This raises hopes for a cure of Rett syndrome and related MeCP2 deficiency disorders of the autistic spectrum.
Abuhatzira
Liron
L
Department of Cellular Biochemistry and Human Genetics, Hebrew University Medical School, Ein Kerem, Jerusalem 91120, Israel.
Shemer
Ruth
R
Razin
Aharon
A
D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D051379:Mice; D015518:Rett Syndrome / Q000235:genetics / Q000378:metabolism; D014404:Tubulin / Q000235:genetics*
D051783:Methyl-CpG-Binding Protein 2; D014404:Tubulin