Controlling tissue patterning by translational regulation of signaling transcripts through the core translation factor eIF3c

Dev Cell. 2021 Nov 8;56(21):2928-2937.e9. doi: 10.1016/j.devcel.2021.10.009.

Abstract

Although gene expression is tightly regulated during embryonic development, the impact of translational control has received less experimental attention. Here, we find that eukaryotic translation initiation factor-3 (eIF3) is required for Shh-mediated tissue patterning. Analysis of loss-of-function eIF3 subunit c (Eif3c) mice reveal a unique sensitivity to the Shh receptor patched 1 (Ptch1) dosage. Genome-wide in vivo enhanced cross-linking immunoprecipitation sequence (eCLIP-seq) shows unexpected specificity for eIF3 binding to a pyrimidine-rich motif present in subsets of 5'-UTRs and a corresponding change in the translation of these transcripts by ribosome profiling in Eif3c loss-of-function embryos. We further find a transcript specific effect in Eif3c loss-of-function embryos whereby translation of Ptch1 through this pyrimidine-rich motif is specifically sensitive to eIF3 amount. Altogether, this work uncovers hidden specificity of housekeeping translation initiation machinery for the translation of key developmental signaling transcripts.

Keywords: Shh signaling; eCLIP; limb development; mRNA translation; neural tube specification; ribosome profiling.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Eukaryotic Initiation Factor-3 / genetics
  • Eukaryotic Initiation Factor-3 / metabolism*
  • Humans
  • Mice
  • Protein Biosynthesis / physiology*
  • Protein Processing, Post-Translational / physiology*
  • RNA, Messenger / genetics
  • Ribosomes / metabolism*
  • Signal Transduction / physiology

Substances

  • Eukaryotic Initiation Factor-3
  • RNA, Messenger