EFTUD2 Regulates Cortical Morphogenesis via Modulation of Caspase-3 and Aifm1 Splicing Pathways

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Elongation Factor Tu GTP-Binding Domain Containing 2 (EFTUD2) is a spliceosomal GTPase linked to Mandibulofacial Dysostosis with Microcephaly (MFDM).
• The precise role of EFTUD2 in cerebral development and MFDM pathogenesis remains unclear.

Purpose of the Study:

• To investigate the function of EFTUD2 in cerebral development.
• To elucidate the molecular mechanisms underlying EFTUD2's role in neurodevelopmental disorders like MFDM.

Main Methods:

• Generated murine models with conditional Eftud2 ablation and introduced pathogenic human EFTUD2 variants into neural stem cells (NSCs).
• Utilized transcriptomic and immunofluorescence analyses to assess cellular and molecular changes.
• Employed RNA co-immunoprecipitation, transcriptome sequencing, and splicing assays to identify molecular interactions and functional consequences.

Main Results:

• Eftud2 deficiency in embryonic NSCs caused cortical disorganization and microcephaly.
• Pathogenic EFTUD2 variants led to significant neuronal loss.
• EFTUD2 deficiency activates apoptotic pathways by regulating the alternative splicing of Caspase3 and Aifm1 transcripts, generating pro-apoptotic isoforms.

Conclusions:

• EFTUD2 is critical for maintaining apoptotic balance during corticogenesis.
• Defective splicing regulation by EFTUD2 is the molecular basis of MFDM.
• Findings offer insights for diagnosing and treating neurodevelopmental disorders associated with EFTUD2 dysfunction.