Wnt regulates amino acid transporter Slc7a5 constraining 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/?-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.