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

Kotaro Fujii; Olena Zhulyn; Gun Woo Byeon; Naomi R Genuth; Craig H Kerr; Erin M Walsh; Maria Barna

doi:10.1016/j.devcel.2021.10.009

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.

Authors

Kotaro Fujii¹, Olena Zhulyn², Gun Woo Byeon³, Naomi R Genuth⁴, Craig H Kerr², Erin M Walsh⁵, Maria Barna⁶

Affiliations

¹ Department of Genetics, Stanford University, Stanford, CA 94305, USA; Center for Neurogenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA. Electronic address: kotaro.fujii@ufl.edu.
² Department of Genetics, Stanford University, Stanford, CA 94305, USA.
³ Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Electrical and Computer Engineering, University of Washington, Seattle, WA 98195, USA.
⁴ Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
⁵ Center for Neurogenetics, University of Florida, Gainesville, FL 32610, USA; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
⁶ Department of Genetics, Stanford University, Stanford, CA 94305, USA. Electronic address: mbarna@stanford.edu.

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

Grants and funding

R01 HD086634/HD/NICHD NIH HHS/United States