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

Pervasive translational regulation of the cell signalling circuitry underlies mammalian development.

Fujii K1,2, Shi Z1,2, Zhulyn O1,2, Denans N1,2, Barna M1,2.

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Department of Developmental Biology, Stanford University, Stanford, California 94305, USA.
Department of Genetics, Stanford University, Stanford, California 94305, USA.


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.

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