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An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons

Ji-Ann Lee1, Zhen-Zhi Tang, Douglas L Black

  • 1Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90095, USA.

Genes & Development
|September 19, 2009
PubMed

Insights

Chronic depolarization alters neuronal splicing via CaM kinase IV. The splicing regulator Fox-1 (RNA-binding protein) changes localization, enabling adaptation to sustained stimuli.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Neuronal depolarization and CaM kinase IV signaling impact alternative splicing of synaptic protein transcripts.
  • Splicing regulation in neurons involves CaM kinase-responsive elements and Fox (Feminizing gene on X) protein family members.
  • Fox protein targets often include proteins crucial for synaptic activity.

Purpose of the Study:

  • To investigate the role of Fox-1/Ataxin 2-Binding Protein 1 (A2BP1) in counteracting splicing changes induced by chronic neuronal depolarization.
  • To elucidate the mechanism by which Fox-1 regulates splicing in response to sustained stimuli.

Main Methods:

  • Analysis of alternative splicing in neuronal transcripts under chronic depolarization conditions.
  • Investigating the effect of depolarization on Fox-1 expression and subcellular localization.
  • Examining the functional consequences of Fox-1 isoform switching on target exon splicing.

Main Results:

  • Fox-1/A2BP1 counteracts the splicing alterations caused by chronic depolarization.
  • Depolarization represses exon 19 of Fox-1, leading to the production of a nuclear-localized isoform.
  • Increased nuclear Fox-1 reactivates previously repressed neuronal target exons, such as NMDA receptor 1 exon 5.

Conclusions:

  • A novel mechanism for slow splicing modulation during cellular adaptation to chronic stimuli is revealed.
  • The subcellular localization of splicing regulators can be controlled by their own alternative splicing.
  • This process allows neurons to adapt their proteome in response to sustained environmental changes.

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