A Rapid Induction Mechanism for Lin28a in Trophic Responses

Alexandra M. Amen, Claudia R. Ruiz-Garzon, Jay Shi, Megha Subramanian, Daniel L. Pham, Mollie K. Meffert

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)490-503.e7
JournalMolecular cell
Volume65
Issue number3
DOIs
StatePublished - Feb 2 2017

Keywords

  • BDNF
  • Dicer
  • Let-7 microRNA
  • Lin28
  • MAPK
  • TRBP
  • dendritic spine
  • microRNA biogenesis
  • synaptic plasticity
  • trophic response

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Amen, A. M., Ruiz-Garzon, C. R., Shi, J., Subramanian, M., Pham, D. L., & Meffert, M. K. (2017). A Rapid Induction Mechanism for Lin28a in Trophic Responses. Molecular cell, 65(3), 490-503.e7. https://doi.org/10.1016/j.molcel.2016.12.025