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Rett syndrome (RTT) is a debilitating neurodevelopmental disorder caused by mutations in the MECP2 gene. To facilitate the study of cellular mechanisms in human cells, we established several human stem cell lines: human embryonic stem cell (hESC) line carrying the common T158M mutation (MECP2T158M/T158M ), hESC line expressing no MECP2 (MECP2-KO), congenic pair of wild-type and mutant RTT patient-specific induced pluripotent stem cell (iPSC) line carrying the V247fs mutation (V247fs-WT and V247fs-MT), and iPSC line in which the V247fs mutation was corrected by CRISPR/Cas9-based genome editing (V247fs-MT-correction). Detailed analyses of forebrain neurons differentiated from these human stem cell lines revealed genotype-dependent quantitative phenotypes in neurite growth, dendritic complexity, and mitochondrial function. At the molecular level, we found a significant reduction in the level of CREB and phosphorylated CREB in forebrain neurons differentiated from MECP2T158M/T158M , MECP2-KO, and V247fs-MT stem cell lines. Importantly, overexpression of CREB or pharmacological activation of CREB signaling in those forebrain neurons rescued the phenotypes in neurite growth, dendritic complexity, and mitochondrial function. Finally, pharmacological activation of CREB in the female Mecp2 heterozygous mice rescued several behavioral defects. Together, our study establishes a robust in vitro platform for consistent quantitative evaluation of genotype-dependent RTT phenotypes, reveals a previously unappreciated role of CREB signaling in RTT pathogenesis, and identifies a potential therapeutic target for RTT.SIGNIFICANCE STATEMENT Our study establishes a robust human stem cell-based platform for consistent quantitative evaluation of genotype-dependent Rett syndrome (RTT) phenotypes at the cellular level. By providing the first evidence that enhancing cAMP response element binding protein signaling can alleviate RTT phenotypes both in vitro and in vivo, we reveal a previously unappreciated role of cAMP response element binding protein signaling in RTT pathogenesis, and identify a potential therapeutic target for RTT.
Pubmed ID: 28270572 RIS Download
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This polyclonal targets CREB
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View all literature mentionsA nonprofit organization offering research and clinical grade pluripotent stem cell lines, cytogenetic testing, quality control testing and cell banking services to researchers worldwide. The organization is focused on enhancing and expanding the study of human pluripotent stem cells by supporting basic research; establishing research protocols; creating and distributing cell lines; providing training to scientists worldwide; and supporting efforts to unlock the therapeutic potential of stem cell technologies. As home to the Wisconsin International Stem Cell (WISC) Bank, and previously the first US National Stem Cell Bank, WiCell serves the worldwide scientific stem cell community through banking, characterization, and distribution of stem cell lines as well as providing technical support. WiCell also offers cytogenetic services, quality control testing services and clinical grade cell lines to researchers across the globe.
View all literature mentionsThis polyclonal targets CREB
View all literature mentionsThis monoclonal targets MeCP2 (D4F3) XP Rabbit mAb
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