Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alternative splicing is widespread in the mammalian brain.
• Understanding its role in neural development is crucial.

Purpose of the Study:

• To investigate the functional role of alternative splicing in neural progenitor cell (NPC) differentiation.
• To identify key regulators and targets of alternative splicing during cerebral cortex development.

Main Methods:

• Analysis of purified NPCs and neurons from developing mammalian cerebral cortices.
• Identification and characterization of differentially spliced exons and their protein domain alterations.
• Investigation of the antagonistic roles of Ptbp1 and Rbfox proteins in regulating splicing.
• Analysis of a human mutation affecting splicing and its link to brain malformation.

Main Results:

• Hundreds of differentially spliced exons were identified, particularly affecting cytoskeletal proteins and potentially harboring disease-causing mutations.
• Ptbp1 and Rbfox proteins were shown to antagonistically control the NPC-to-neuron transition by regulating neuron-specific exons.
• Ptbp1 maintains apical progenitors by suppressing a poison exon of Flna, while Rbfox proteins promote neuronal differentiation by altering Ninein splicing.
• A human intronic mutation in a PTBP1-binding site disrupted FLNA exon skipping, leading to a brain-specific malformation.

Conclusions:

• Dynamic control of alternative splicing is essential for cell fate determination during cerebral cortical development.
• Dysregulation of splicing, as exemplified by the FLNA mutation, can lead to brain malformations.
• Ptbp1 and Rbfox are key antagonistic regulators of the neural progenitor cell to neuron transition via alternative splicing.