Pervasive translational regulation of the cell signalling circuitry underlies mammalian development

Nat Commun. 2017 Feb 14:8:14443. doi: 10.1038/ncomms14443.

Abstract

The degree and dynamics of translational control during mammalian development remain poorly understood. Here we monitored translation of the mammalian genome as cells become specified and organize into tissues in vivo. This identified unexpected and pervasive translational regulation of most of the core signalling circuitry including Shh, Wnt, Hippo, PI3K and MAPK pathways. We further identify and functionally characterize a complex landscape of upstream open reading frames (uORFs) across 5'-untranslated regions (UTRs) of key signalling components. Focusing on the Shh pathway, we demonstrate the importance of uORFs within the major SHH receptor, Ptch1, in control of cell signalling and neuronal differentiation. Finally, we show that the expression of hundreds of mRNAs underlying critical tissue-specific developmental processes is largely regulated at the translation but not transcript levels. Altogether, this work reveals a new layer of translational control to major signalling components and gene regulatory networks that diversifies gene expression spatially across developing tissues.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / genetics
  • 5' Untranslated Regions / physiology
  • Animals
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Female
  • Gene Expression Regulation, Developmental*
  • Hedgehog Proteins / metabolism
  • Hippo Signaling Pathway
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mammals / genetics*
  • Mammals / metabolism*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • NIH 3T3 Cells
  • Open Reading Frames / genetics
  • Open Reading Frames / physiology
  • Patched-1 Receptor / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Biosynthesis
  • Protein Processing, Post-Translational / genetics*
  • Protein Processing, Post-Translational / physiology*
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Processing, Post-Transcriptional
  • RNA, Messenger / metabolism
  • Sequence Alignment
  • Wnt Signaling Pathway

Substances

  • 5' Untranslated Regions
  • Hedgehog Proteins
  • Intercellular Signaling Peptides and Proteins
  • Patched-1 Receptor
  • RNA, Messenger
  • Shh protein, mouse
  • Protein Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase Kinases