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

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 wildtype 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.