TGF-β/Nodal signaling boosts glucose uptake during mesendoderm differentiation by inducing a transmembrane micropeptide. TGF-β/Nodal signaling boosts glucose uptake during mesendoderm differentiation by inducing a transmembrane micropeptide

TGF-β signaling is a central regulator of early development in metazoans, yet our understanding of the scope of TGF-β signaling’s downstream targets and associated physiological mechanisms in specifying developmentally appropriate cell fates is far from complete. Here, we found that a highly conserved, primitive-streak-specific micropeptide is a direct target of TGF-b/Nodal signaling. This transmembrane micropeptide (NEMEP) is essential for mesendoderm differentiation. Depletion of NEMEP impaired mesendoderm differentiation and caused a significant decrease in glucose uptake, while TGF-β signaling enhances glucose uptake in a NEMEP-dependent manner. Biochemically, we show that NEMEP promotes glucose uptake through its interactions with GLUT1/3. Thus, beyond expanding the scope of known TGF-β signaling targets in early development and showing that this target micropeptide augments the glucose uptake function of major glucose transporters during mesendoderm differentiation, our study provides a clear example for the direct functional impact of altered metabolism on cell fate determination in early embryogenesis. Overall design: Identifiy TGF-β responsive lncRNA/micropeptide, dissect function and molecular mechanism of a micropeptide in mesendoderm differentiation

转化生长因子β（TGF-β）信号通路是后生动物（metazoans）早期发育的核心调控因子，然而我们对于TGF-β信号通路在调控发育适宜的细胞命运过程中所涉及的下游靶点范围及相关生理机制的认知仍远未完善。本研究发现，一种高度保守的原条（primitive streak）特异性微肽（micropeptide）是TGF-β/结节（Nodal）信号通路的直接靶点。该跨膜微肽（NEMEP）是中内胚层（mesendoderm）分化所必需的。敲低NEMEP会损害中内胚层分化，并显著降低葡萄糖摄取（glucose uptake）；而TGF-β信号通路则以NEMEP依赖的方式增强葡萄糖摄取。生化实验表明，NEMEP通过与葡萄糖转运蛋白1/3（GLUT1/3）相互作用促进葡萄糖摄取。综上，本研究不仅拓展了早期发育中已知的TGF-β信号通路靶点范围，证实该靶点微肽可在中内胚层分化过程中增强主要葡萄糖转运蛋白的葡萄糖摄取功能，同时为代谢改变在早期胚胎发生过程中直接影响细胞命运决定提供了明确例证。研究整体设计：鉴定TGF-β响应的长链非编码RNA（lncRNA）/微肽，解析该微肽在中内胚层分化中的功能与分子机制。