Association of dysfunctional synapse defective 1 (SYDE1) with restricted fetal growth – SYDE1 regulates placental cell migration and invasion

The GCM1 transcription factor regulates trophoblast differentiation and function during placentation. Decreased GCM1 expression is associated with preeclampsia, suggesting that abnormal expression of GCM1 target genes may contribute to the pathogenesis of pregnancy complications. Here we identified a novel GCM1 target gene SYDE1, which encodes a RhoGAP highly expressed in human placenta, and demonstrated that SYDE1 promotes cytoskeletal remodeling and cell migration and invasion. Importantly, genetic ablation of murine Syde1 results in small fetuses and placentas with aberrant phenotypes in the placental-yolk sac barrier, maternal-trophoblast interface, and placental vasculogenesis. Correspondingly, microarray analysis revealed altered expression of the renin-angiotensin system in Syde1-knockout placenta. As pregnancy proceeds, growth restriction of the Syde1-/- fetuses and placentas continues with elevated expression of the Syde1 homologue Syde2 in placenta. Syde2 may compensate for the loss of Syde1 function because SYDE2, but not the GAP-dead SYDE2 mutant, reverses migration and invasion activities of SYDE1-knockdown JAR trophoblast cells. Clinically, we further detected decreased SYDE1 expression in preterm and term IUGR placentas compared with gestational age-matched controls. Our study reveals a novel mechanism for GCM1 and SYDE1 in regulation of trophoblast cell migration and invasion during placental development and that decreased SYDE1 expression is associated with IUGR.