Glycolysis-Independent Glucose Metabolism Distinguishes TE from ICM Fate during Mammalian Embryogenesis

• Published in: Developmental cell 2020-04, Vol.53 (1), p.9-26.e4
• Main Authors: Chi, Fangtao, Sharpley, Mark S., Nagaraj, Raghavendra, Roy, Shubhendu Sen, Banerjee, Utpal
• Format: Article
• Language: English
• Subjects: Animals; Blastocyst - metabolism; Cell Differentiation - physiology; developmental metabolism; Embryo, Mammalian - metabolism; Embryonic Development - physiology; Gene Expression Regulation, Developmental - physiology; glucose; Glucose - metabolism; Glycolysis - physiology; hexosamine biosynthetic pathway; Homeodomain Proteins - metabolism; Mice; morula blastocyst; pentose phosphate pathway; preimplantation embryo; S1P signaling; Tfap2c; Transcription Factors - metabolism; trophectoderm; YAP1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.02.015

The mouse embryo undergoes compaction at the 8-cell stage, and its transition to 16 cells generates polarity such that the outer apical cells are trophectoderm (TE) precursors and the inner cell mass (ICM) gives rise to the embryo. Here, we report that this first cell fate specification event is controlled by glucose. Glucose does not fuel mitochondrial ATP generation, and glycolysis is dispensable for blastocyst formation. Furthermore, glucose does not help synthesize amino acids, fatty acids, and nucleobases. Instead, glucose metabolized by the hexosamine biosynthetic pathway (HBP) allows nuclear localization of YAP1. In addition, glucose-dependent nucleotide synthesis by the pentose phosphate pathway (PPP), along with sphingolipid (S1P) signaling, activates mTOR and allows translation of Tfap2c. YAP1, TEAD4, and TFAP2C interact to form a complex that controls TE-specific gene transcription. Glucose signaling has no role in ICM specification, and this process of developmental metabolism specifically controls TE cell fate. [Display omitted] •TE formation in mouse embryos is controlled by glucose metabolism activating CDX2•Glycolysis is dispensable, and glucose is not required for amino acid or lipid synthesis•Nucleotides synthesized from glucose, along with S1P, activate mTOR and TFAP2C•Glucose metabolism by the HBP controls YAP1, which, together with TFAP2C, activates CDX2 Distinct trophectoderm (TE) and inner cell mass (ICM) precursors are first evident in the compacted morula stage. Chi et al. show that glucose metabolism controls this early developmental event. Glucose metabolized by multiple pathways initiates signaling and transcriptional events that control TE but not ICM cell fate.