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

Fingerprint

Brain-Derived Neurotrophic Factor
Growth
Mitogen-Activated Protein Kinases
Dendritic Spines
RNA-Binding Proteins
RNA Interference
Protein Binding
Cues
Intercellular Signaling Peptides and Proteins
Phosphorylation
trans-activation responsive RNA-binding protein
HIV
Gene Expression
Neurons
Proteins
Cell Plasticity

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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

A Rapid Induction Mechanism for Lin28a in Trophic Responses. / Amen, Alexandra M.; Ruiz-Garzon, Claudia R.; Shi, Jay; Subramanian, Megha; Pham, Daniel L.; Meffert, Mollie K.

In: Molecular Cell, Vol. 65, No. 3, 02.02.2017, p. 490-503.e7.

Research output: Contribution to journalArticle

Amen, AM, Ruiz-Garzon, CR, Shi, J, Subramanian, M, Pham, DL & Meffert, MK 2017, 'A Rapid Induction Mechanism for Lin28a in Trophic Responses', Molecular Cell, vol. 65, no. 3, pp. 490-503.e7. https://doi.org/10.1016/j.molcel.2016.12.025
Amen AM, Ruiz-Garzon CR, Shi J, Subramanian M, Pham DL, Meffert MK. A Rapid Induction Mechanism for Lin28a in Trophic Responses. Molecular Cell. 2017 Feb 2;65(3):490-503.e7. https://doi.org/10.1016/j.molcel.2016.12.025
Amen, Alexandra M. ; Ruiz-Garzon, Claudia R. ; Shi, Jay ; Subramanian, Megha ; Pham, Daniel L. ; Meffert, Mollie K. / A Rapid Induction Mechanism for Lin28a in Trophic Responses. In: Molecular Cell. 2017 ; Vol. 65, No. 3. pp. 490-503.e7.
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