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A Rapid Induction Mechanism for Lin28a in Trophic Responses.

Molecular cell | Feb 2, 2017

Environmental cues provoke rapid transitions in gene expression to support growth and cellular plasticity through incompletely understood mechanisms. Lin28 RNA-binding proteins have evolutionarily conserved roles in post-transcriptional coordination of pro-growth gene expression, but signaling pathways allowing trophic stimuli to induce Lin28 have remained uncharacterized. We find that Lin28a protein exhibits rapid basal turnover in neurons and that mitogen-activated protein kinase (MAPK)-dependent phosphorylation of the RNA-silencing factor HIV TAR-RNA-binding protein (TRBP) promotes binding and stabilization of Lin28a, but not Lin28b, with an accompanying reduction in Lin28-regulated miRNAs, downstream of brain-derived neurotrophic factor (BDNF). Binding of Lin28a to TRBP in vitro is also enhanced by phospho-mimic TRBP. Further, phospho-TRBP recapitulates BDNF-induced neuronal dendritic spine growth in a Lin28a-dependent manner. Finally, we demonstrate MAPK-dependent TRBP and Lin28a induction, with physiological function in growth and survival, downstream of diverse growth factors in multiple primary cell types, supporting a broad role for this pathway in trophic responses.

Pubmed ID: 28132840 RIS Download

Mesh terms: Animals | Brain-Derived Neurotrophic Factor | Cell Proliferation | Cell Survival | Dendritic Spines | HEK293 Cells | Hippocampus | Humans | Macrophages, Peritoneal | Mice | Mitogen-Activated Protein Kinases | Neurons | Phosphorylation | RNA-Binding Proteins

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