Elsevier

Stem Cell Research

Volume 31, August 2018, Pages 135-146
Stem Cell Research

NOSTRIN: A novel modulator of trophoblast giant cell differentiation

https://doi.org/10.1016/j.scr.2018.07.023Get rights and content
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open access

Highlights

  • NOSTRIN is primarily expressed by trophoblast giant cells of the developing placenta.

  • Differentiation of trophoblast stem cells induces NOSTRIN expression that enhances TGC formation and trophoblast invasion.

  • NOSTRIN promotes actin polymerization, augments formation of ternary complex with N-WASP and dynamin in trophoblast cells.

  • NOSTRIN interacts with Cdk1 and enhances T14, Y15 phosphorylation.

  • SH3 domain deleted NOSTRIN fails to elicit its response in trophoblast cells.

Abstract

Differentiation-dependent expression of NOSTRIN in murine trophoblast cells prompted investigation on NOSTRIN's function in trophoblast differentiation. We show here that NOSTRIN levels increased in both mouse and rat placenta during gestation. NOSTRIN expression was not co-related to expression of eNOS precluding its eNOS mediated function. NOSTRIN transcripts were identified in trophoblast cells of the placenta, predominantly in trophoblast giant cells (TGC). Precocious over-expression of NOSTRIN during differentiation of trophoblast stem cells led to up-regulation of genetic markers associated with invasion (Prl4a1, Prl2a1) and TGC formation (Prl2c2, Prl3d1, Prl3b1). The functional consequence of NOSTRIN over-expression was increased TGC formation and trophoblast cell invasion. Furthermore, number of polyploid TGCs that arise by endoreduplication, were higher in presence of NOSTRIN. Early induction of NOSTRIN was associated with substantial decrease in G/F actin ratio and augmentation of N-WASP-Dynamin-NOSTRIN ternary complex formation that might be partially responsible for nucleation of actin filaments. NOSTRIN also formed a complex with Cdk1 and increased phosphorylation of T14 and Y15 residues that inhibits cytokinesis. Interestingly, SH3 domain deleted NOSTRIN was ineffective in eliciting NOSTRIN's function in differentiating trophoblast cells. These findings demonstrate that NOSTRIN potentiates trophoblast differentiation towards TGC trajectory that is critical for hemochorial placentation.

Keywords

NOSTRIN
Trophoblast stem cell
Differentiation
Giant cell
Invasion
Actin polymerization

Abbreviations

ICM
Inner cell mass
TE
Trophoectoderm
TSC
Trophoblast stem cell (TSC)
NOSTRIN
Nitric Oxide Synthase Trafficking INducer
eNOS
endothelial nitric oxide synthase
NO
nitric oxide
PE
pre-eclampsia
PIH
pregnancy-induced hypertension
JZ
Junctional zone
LZ
Labyrinth zone
TGC
trophoblast giant cell
MEF
mouse embryonic fibroblasts

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