Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Rett syndrome (RTT) is a severe neurological disorder causing intellectual disability, primarily linked to mutations in the methyl-CpG binding protein 2 (MeCP2) gene.
• The precise molecular mechanisms driving RTT pathogenesis remain incompletely understood despite extensive research.

Purpose of the Study:

• To elucidate the role of MeCP2 in higher-order protein complex assembly and its implications in Rett syndrome.
• To investigate how MeCP2 mutations affect protein complex formation, RNA splicing, and synaptic function.

Main Methods:

• Identification of MeCP2 as a component of the Rbfox/LASR protein complex.
• Analysis of MeCP2/Rbfox/LASR complex assembly in RTT mouse models.
• In vitro and cell-based assays to assess MeCP2 mutant properties and condensate formation.

Main Results:

• Defective MeCP2 in RTT models disrupts the MeCP2/Rbfox/LASR complex, impairing Rbfox protein binding to pre-mRNAs.
• Aberrant splicing of Nrxns and Nlgn1, crucial for synaptic plasticity, is observed in RTT models.
• MeCP2 disease mutants exhibit defective phase separation properties, failing to form functional condensates with Rbfox proteins.

Conclusions:

• MeCP2 functions as a key subunit in the higher-order Rbfox/LASR complex, essential for proper RNA splicing.
• Impaired MeCP2 function and disease mutations disrupt complex assembly and condensate formation, linking splicing defects to RTT.
• These findings provide novel insights into RTT pathogenesis by connecting MeCP2's role in complex formation and splicing regulation.