Wnt regulates amino acid transporter Slc7a5 and so constrains the integrated stress response in mouse embryos.

Nadège Poncet,Melanie Febrer,Peter M Taylor,Gail A Singer,Kate G Storey,Terry P Yamaguchi,Alwyn Dady,Pamela A Halley,Yun‐Bo Shi,Christopher Lipina,Marek Gierliński

doi:10.15252/embr.201948469

Abstract

Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis. Here, we show that the amino acid transporter Slc7a5/Lat1 is highly expressed in tissues undergoing morphogenesis and that Slc7a5‐null mouse embryos have profound neural and limb bud outgrowth defects. Slc7a5‐null neural tissue exhibited aberrant mTORC1 activity and cell proliferation; transcriptomics, protein phosphorylation and apoptosis analyses further indicated induction of the integrated stress response as a potential cause of observed defects. The pattern of stress response gene expression induced in Slc7a5‐null embryos was also detected at low level in wild‐type embryos and identified stress vulnerability specifically in tissues undergoing morphogenesis. The Slc7a5‐null phenotype is reminiscent of Wnt pathway mutants, and we show that Wnt/β‐catenin loss inhibits Slc7a5 expression and induces this stress response. Wnt signalling therefore normally supports the metabolic demands of morphogenesis and constrains cellular stress. Moreover, operation in the embryo of the integrated stress response, which is triggered by pathogen‐mediated as well as metabolic stress, may provide a mechanistic explanation for a range of developmental defects.

Highlights

Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis
The spatial and temporal expression pattern of the large neutral amino acids (LNAAs) transporter Slc7a5 was assessed by mRNA in situ hybridisation in whole mouse embryos from early primitive streak stages (Fig 1); probe specificity was assessed in Slc7a5-null embryos, where no signal was detected (Appendix Fig S1)
By elucidating the expression pattern, requirement and regulation of the amino acid transporter Slc7a5, this study uncovers a mechanism by which cell metabolism is regulated by developmental signalling in the mammalian embryo

Summary

Introduction

Amino acids are essential for cellular metabolism, and it is important to understand how nutrient supply is coordinated with changing energy requirements during embryogenesis. We show that the amino acid transporter Slc7a5/Lat is highly expressed in tissues undergoing morphogenesis and that Slc7a5-null mouse embryos have profound neural and limb bud outgrowth defects. Slc7a5-null neural tissue exhibited aberrant mTORC1 activity and cell proliferation; transcriptomics, protein phosphorylation and apoptosis analyses further indicated induction of the integrated stress response as a potential cause of observed defects. The pattern of stress response gene expression induced in Slc7a5-null embryos was detected at low level in wild-type embryos and identified stress vulnerability in tissues undergoing morphogenesis. The Slc7a5-null phenotype is reminiscent of Wnt pathway mutants, and we show that Wnt/b-catenin loss inhibits Slc7a5 expression and induces this stress response. Operation in the embryo of the integrated stress response, which is triggered by pathogen-mediated as well as metabolic stress, may provide a mechanistic explanation for a range of developmental defects

Methods

Results

Conclusion