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Specific isoform of p38 MAPK and splicing regulator Pasilla integrate systemic and external stimuli to control intron retention and long-term memory
Park, Younshim
Park, Younshim
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Abstract
Intron retention (IR) has emerged as a gene-regulatory mechanism underlying many physiological processes such as development, immunity, or neuronal plasticity. However, it remains largely unknown how IR is regulated. In Drosophila melanogaster, a specific variant of cytoplasmic polyA-element binding protein family member Orb2A, is required for memory stabilization. In efforts to understand how expression of Orb2A is regulated, we discovered that specific retained intron can be transiently spliced to allow spatial and temporal integration of signals to acutely control protein expression in the nervous system. We found that convergence of specific sensory stimuli (sugar and odor) and internal state (hunger) converts intron-containing, non-protein coding unspliced Orb2A mRNA into a protein-coding spliced Orb2A mRNA. The regulated removal of the Orb2A intron is necessary to form long-term memory, and the regulated splicing is mediated by the neuronal splicing regulator Pasilla, the Drosophila orthologue of mammalian Nova. These observations prompted us to ask what cellular processes integrate systemic and sensory stimuli and regulate Pasilla activity. We found that Pasilla is a phospho-protein and p38 mitogen-activated protein kinase (p38MAPK) as a potential kinase of Pasilla. Inhibition of p38 MAPK decreases Pasilla phosphorylation and Orb2A splicing and protein expression. There are three p38 MAPKs in Drosophila: p38a, p38b, and p38c. We found that among these three p38 variants, p38a has highest affinity for Pasilla protein. p38a MAPK is a nonessential gene, however, knock down of p38a results in a selective impairment in long-term memory. We postulate that p38a MAPK acts as a sensor that integrates systemic stimuli such as starvation and specific sensory stimuli to effect Pasilla phosphorylation and splicing of retained introns to control long-term memory formation.
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2020-01-01
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University of Kansas
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Keywords
Neurobiology, Molecular biology, Alternative splicing, intron retention, long-term memory, Orb2 aggregation, p38MAPK, Pasilla