Pervasive translational regulation of the cell signalling circuitry underlies mammalian development

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.

Heterogeneous Ribosomes Preferentially Translate Distinct Subpools of mRNAs Genome-wide

“…Our study of ribosome heterogeneity within mESCs therefore serves as a foundation to future research. For example, a recent study has revealed tissue-specific programs of translational control during mammalian embryonic development (Fujii et al, 2017). An important immediate question is to determine whether a selective translational landscape of specific types of ribosomes bearing or missing certain RPs exists during the course of cellular differentiation and between different cell and tissue types where the degree of ribosome heterogeneity could be even more extensive.…”

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

“…While identity of those mRNAs has to be determined by future experiments, one should mention that many key components of the PI3K/MTOR signaling pathway appear to have highly inefficient translation initiation, at least, in mouse embryonic stem cells (Fujii et al . ). Interestingly, reduced activity of the PI3K/MTOR pathway was observed after inhibition of neuronal ribosome synthesis (Slomnicki et al .…”

An emerging role for the ribosome as a nexus for post-translational modifications

“…Finally, establishing antibodies that can recognize site-specific PTMs will help to understand the distribution of these RP PTMs within different tissues, during different physiological states, or during the course of embryonic development. It has been recently shown that translation of the mammalian genome is intricately controlled in space and time [87]. The approaches outlined here to identify RP PTMs and to characterize their functional consequences are likely to reveal the potential dynamics of how ribosome modifications may directly influence protein expression within cells and developing organisms.…”