Parallel evolution of a splicing program controlling neuronal excitability in flies and mammals

Area of Science:

• Molecular Biology
• Neuroscience
• Evolutionary Biology

Background:

• Alternative splicing significantly contributes to neuronal transcriptomic complexity across animal evolution.
• Understanding the mechanisms governing the assembly and evolution of this regulatory layer is crucial.

Purpose of the Study:

• To characterize the neuronal microexon program in Drosophila and compare it with mammalian systems.
• To investigate the role of the enhancer of microexons (eMIC) in neuronal function and evolution.

Main Methods:

• Comparative analysis of neuronal microexon programs in Drosophila and mammals.
• Investigating the posttranscriptional processing of the enhancer of microexons (eMIC) domain in Srrm234.
• Utilizing neuronal imaging and cell type-specific rescues to assess functional consequences.
• Genome-wide analysis of exon skipping events.

Main Results:

• The neuronal splicing program is neuron-specific in nonvertebrate bilaterians, mediated by eMIC processing regulated by Elav/Fne in Drosophila.
• eMIC deficiency or misexpression causes widespread neurological alterations linked to impaired neuronal activity.
• Defects are associated with genome-wide skipping of neural exons, particularly those in ion channels.
• No overlap in eMIC-regulated exons was found between flies and mice, indicating independent evolution.

Conclusions:

• Ancient posttranscriptional programs, like eMIC regulation, can evolve independently in different phyla.
• These programs fine-tune distinct cellular modules while maintaining cell-type specificity.
• The study highlights the diverse evolutionary paths of gene regulation in neuronal complexity.