CREB Signaling Is Involved in Rett Syndrome Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• Rett syndrome (RTT) is a severe neurodevelopmental disorder linked to mutations in the MECP2 gene.
• Understanding RTT cellular mechanisms requires robust human cell models.
• Existing models lack comprehensive genotype-specific phenotypic evaluation.

Purpose of the Study:

• To establish and validate human stem cell lines for studying RTT.
• To investigate genotype-dependent cellular phenotypes in RTT.
• To identify molecular pathways and potential therapeutic targets for RTT.

Main Methods:

• Generation of human embryonic stem cell (hESC) and induced pluripotent stem cell (iPSC) lines with specific MECP2 mutations (T158M, V247fs) and corrections.
• Differentiation of stem cells into forebrain neurons for phenotypic analysis (neurite growth, dendritic complexity, mitochondrial function).
• Molecular analysis of CREB (cAMP response element binding protein) signaling and rescue experiments in vitro and in vivo (Mecp2 heterozygous mice).

Main Results:

• Human stem cell-derived neurons exhibited genotype-dependent defects in neurite growth, dendritic complexity, and mitochondrial function.
• Reduced levels of CREB and phosphorylated CREB were observed in RTT model neurons.
• Overexpression or pharmacological activation of CREB rescued cellular phenotypes in vitro and behavioral deficits in vivo.

Conclusions:

• Established a robust human stem cell platform for quantitative RTT phenotype evaluation.
• Demonstrated a critical role for CREB signaling in RTT pathogenesis.
• Identified CREB signaling as a promising therapeutic target for Rett syndrome.