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Wnt regulates amino acid transporter Slc7a5 and so constrains the integrated stress response in mouse embryos.
EMBO Reports ( IF 6.5 ) Pub Date : 2019-12-02 , DOI: 10.15252/embr.201948469
Nadège Poncet 1 , Pamela A Halley 1 , Christopher Lipina 2 , Marek Gierliński 3 , Alwyn Dady 1 , Gail A Singer 1 , Melanie Febrer 4 , Yun-Bo Shi 5 , Terry P Yamaguchi 6 , Peter M Taylor 2 , Kate G Storey 1
Affiliation  

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.

中文翻译:


Wnt 调节氨基酸转运蛋白 Slc7a5,从而限制小鼠胚胎中的综合应激反应。



氨基酸对于细胞代谢至关重要,了解营养供应如何与胚胎发生过程中不断变化的能量需求相协调非常重要。在这里,我们发现氨基酸转运蛋白 Slc7a5/Lat1 在正在进行形态发生的组织中高度表达,并且 Slc7a5 缺失的小鼠胚胎具有严重的神经和肢芽生长缺陷。 Slc7a5缺失的神经组织表现出异常的mTORC1活性和细胞增殖;转录组学、蛋白质磷酸化和细胞凋亡分析进一步表明,综合应激反应的诱导是观察到的缺陷的潜在原因。在野生型胚胎中也检测到低水平的 Slc7a5 缺失胚胎中诱导的应激反应基因表达模式,并特别鉴定了正在经历形态发生的组织中的应激脆弱性。 Slc7a5 缺失表型让人想起 Wnt 通路突变体,我们发现 Wnt/β-catenin 缺失会抑制 Slc7a5 表达并诱导这种应激反应。因此,Wnt 信号传导通常支持形态发生的代谢需求并限制细胞应激。此外,由病原体介导的应激反应和代谢应激反应引发的胚胎综合应激反应的运作可能为一系列发育缺陷提供机制解释。
更新日期:2020-01-07
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