NOSTRIN: A novel modulator of trophoblast giant cell differentiation.

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.