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Published on: September 14, 2021
Nodal/Smad2 signaling sustains developmental pausing by repressing Pparg-mediated lipid metabolism
Giacomo Furlan1, S Bryn Martin1, Brandon Cho1
1Lunenfeld-Tanenbaum Research Institute and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
None:
Mammalian embryonic diapause is a reversible state of pre-implantation dormancy characterized by metabolic rewiring toward lipid usage as energy source. Whether active signaling sustains this dormant state remained unclear. Here, we show that the transforming growth factor- β (TGF-β) pathway, previously thought to only be required post-implantation, is essential for diapause. Nodal signaling is activated and its downstream effector SMAD family member 2 (Smad2) is required during diapause in vivo. Using ex vivo blastocyst and embryonic stem cells models of diapause, we show that Smad2 represses peroxisome proliferator-activated receptor gamma (Pparg), a master regulator of lipid storage. Loss of Smad2-mediated Pparg repression leads to lipid accumulation and is incompatible with pausing. Our findings establish a Nodal-Smad2-Pparg axis that is pivotal for sustaining the transcriptional and metabolic programs of embryonic diapause. This axis may be redeployed in other contexts, including cancer dormancy and metabolic disorders.
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