MeCP2 DIRECTLY REGULATES INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3 EXPRESSION IN BRAINS

Objectives: Rett syndrome (RTT) is a major developmental degeneration characterized by mental retardation and specific autistic behavior. Mutations of the MeCP2 gene, encoding methyl-CpG binding protein 2, cause the disease. The pathomechanism of MeCP2 dysfunction leading to RTT phenotype is unknown. We discovered a novel MeCP2-downstream gene, which could be associated with the disease.

Methods: As materials, we used mecp2-null mice and normal littermates for comparative expression study, and also human samples from Harvard Brain Tissue Resource Center. This study was permitted by the animal ethic committee of our institute and was performed under informed consents.

Results: The promoter of IGFBP3 had a MeCP2 binding site, from the result of chromatin immunoprecipitation. Over-expression of IGFBP3 was observed in mecp2-null mice brains, using real-time PCR analysis. Although the number of IGFBP3-positive cells in the wild-type mouse brain might immunohistochemically decrease with age, mecp2-null mice showed wide distribution of IGFBP3-positive cells and fibers in the cerebral cortex. Western blot analysis showed over-expression of IGFBP3 was not only in mecp2-null mice, but also in human brain with RTT.

Conclusion: Our study indicates that IGFBP3 is a MeCP2- downstream gene and MeCP2 can directly contribute to the transcriptional expression of IGFBP3 in brain. Moreover, pathological features of mecp2-null mice have some similarities of IGFBP3 transgenic mice, which show reduction of early postnatal brain growth. Over-expression of IGFBP3 due to lacking of MeCP2 may lead to delay brain maturation.