Shukla_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2403003121

Reference

Title : NOTUM-mediated WNT silencing drives extravillous trophoblast cell lineage development - Shukla_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2403003121
Author(s) : Shukla V , Moreno-Irusta A , Varberg KM , Kuna M , Iqbal K , Galligos AM , Aplin JD , Choudhury RH , Okae H , Arima T , Soares MJ
Ref : Proc Natl Acad Sci U S A , 121 :e2403003121 , 2024
Abstract :

Trophoblast stem (TS) cells have the unique capacity to differentiate into specialized cell types, including extravillous trophoblast (EVT) cells. EVT cells invade into and transform the uterus where they act to remodel the vasculature facilitating the redirection of maternal nutrients to the developing fetus. Disruptions in EVT cell development and function are at the core of pregnancy-related disease. WNT-activated signal transduction is a conserved regulator of morphogenesis of many organ systems, including the placenta. In human TS cells, activation of canonical WNT signaling is critical for maintenance of the TS cell stem state and its downregulation accompanies EVT cell differentiation. We show that aberrant WNT signaling undermines EVT cell differentiation. Notum, palmitoleoyl-protein carboxylesterase (NOTUM), a negative regulator of canonical WNT signaling, was prominently expressed in first-trimester EVT cells developing in situ and up-regulated in EVT cells derived from human TS cells. Furthermore, NOTUM was required for optimal human TS cell differentiation to EVT cells. Activation of NOTUM in EVT cells is driven, at least in part, by endothelial Per-Arnt-Sim (PAS) domain 1 (also called hypoxia-inducible factor 2 alpha). Collectively, our findings indicate that canonical Wingless-related integration site (WNT) signaling is essential for maintenance of human trophoblast cell stemness and regulation of human TS cell differentiation. Downregulation of canonical WNT signaling via the actions of NOTUM is required for optimal EVT cell differentiation.

PubMedSearch : Shukla_2024_Proc.Natl.Acad.Sci.U.S.A_121_e2403003121
PubMedID: 39325428

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Citations formats

Shukla V, Moreno-Irusta A, Varberg KM, Kuna M, Iqbal K, Galligos AM, Aplin JD, Choudhury RH, Okae H, Arima T, Soares MJ (2024)
NOTUM-mediated WNT silencing drives extravillous trophoblast cell lineage development
Proc Natl Acad Sci U S A 121 :e2403003121

Shukla V, Moreno-Irusta A, Varberg KM, Kuna M, Iqbal K, Galligos AM, Aplin JD, Choudhury RH, Okae H, Arima T, Soares MJ (2024)
Proc Natl Acad Sci U S A 121 :e2403003121