Endogenous RNA-based sensors for neuronal homeostasis and plasticity.
Research Project
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15.02.2021
- 15.02.2023
Neurons undergo profound plastic modifications but, at the same time, retain stable intrinsic properties. This implies sensing, signaling and homeostatic mechanisms that couple signaling to gene regulation. In this proposal I will examine a novel mechanism for transcriptional homeostasis in mammalian neurons. Specifically, I will test the hypothesis that the degradation of a class of intron-containing mRNAs contributes to a sensing mechanism that shapes the neuronal transcriptome. There is strong evidence of the link between mRNA decay factors in the cytoplasm and the regulation of gene transcription in the nuclei. Very recent discoveries link mutant mRNA decay by Nonsense Mediated Decay (NMD) with upregulation of the expression of genes with similar sequences, a process named Genetic Compensation (GC). One recently described class of endogenous transcripts destined for NMD arises from intron retention during alternative splicing . Roles for icRNA in nuclei and cytoplasm have been discovered, but most cytoplasmic icRNA are targeted by NMD, and their functional relevance remains a mystery. In analogy to the genetic compensation mechanism in mutant mRNAs, I hypothesize that degradation of endogenous cytoplasmic icRNAs triggers modifications of the neuronal transcriptome. Thus, cytoplasmic icRNAs would act as sensors for neuronal gene expression that signal the state of the cytosolic transcriptome and translatome back to the nucleus to achieve neuronal homeostasis. Using transgenic mouse lines, adenoviral-mediated knock-down and overexpression of reporter genes in cultured cortical neurons and RNA-Seq I will: (1) check whether GC works in post-mitotic neurons, (2) uncover endogenously degraded mRNA role in gene expression regulation.
