title: A Rapid Induction Mechanism for Lin28a in Trophic Responses.
abstract: 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.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Amen
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Ruiz-Garzon
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shi
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Megha
authors.initials: M
authors.lastname: Subramanian
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Pham
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: mkm@jhmi.edu.
authors.forename: Mollie K
authors.initials: MK
authors.lastname: Meffert
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D049229:Dendritic Spines / Q000378:metabolism*; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000378:metabolism*; D000099253:Trans-Activation Responsive RNA-Binding Protein
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020928:Mitogen-Activated Protein Kinases; D016601:RNA-Binding Proteins; D000099253:Trans-Activation Responsive RNA-Binding Protein; C516326:LIN28B protein, human; C488352:Lin-28 protein, mouse
keywords: BDNF; Dicer; Let-7 microRNA; Lin28; MAPK; TRBP; dendritic spine; microRNA biogenesis; synaptic plasticity; trophic response