Homeobox gene transforming growth factor β-induced factor-1 (TGIF-1) is a regulator of villous trophoblast differentiation and its expression is increased in human idiopathic fetal growth restriction

Abstract

Abnormal trophoblast function is associated with human fetal growth restriction (FGR). Targeted disruption of homeobox gene transforming growth β-induced factor (TGIF-1) results in placental dysfunction in the mouse. The role of human TGIF-1 in placental cell function is unknown. The aims of this study were to determine the expression of TGIF-1 in human idiopathic FGR-affected placentae compared with gestation-matched controls (GMC), to elucidate the functional role of TGIF-1 in trophoblasts and to identify its downstream targets. Real-time PCR and immunoblotting revealed that TGIF-1 mRNA and protein expression was significantly increased in FGR-affected placentae compared with GMC (n = 25 in each group P < 0.05). Immunoreactive TGIF-1 was localized to the villous cytotrophoblasts, syncytiotrophoblast, microvascular endothelial cells and in scattered stromal cells in both FGR and GMC. TGIF-1 inactivation in BeWo cells using two independent siRNA resulted in significantly decreased mRNA and protein of trophoblast differentiation markers, human chorionic gonadotrophin (CGB/hCG), syncytin and 3β-hydroxysteroid dehydrogenase/3β-honest significant difference expression. Our data demonstrate that homeobox gene TGIF-1 is a potential up-stream regulator of trophoblast differentiation and the altered TGIF-1 expression may contribute to aberrant villous trophoblast differentiation in FGR.

An EG-VEGF-Dependent Decrease in Homeobox Gene NKX3.1 Contributes to Cytotrophoblast Dysfunction: A Possible Mechanism in Human Fetal Growth Restriction

“…In our previous studies, we reported that FGR placental villi show an upregulated expression of CGB/βhCG (34,53). The decreased expression of NKX3.1 in FGR, therefore, may have clinical significance in contributing to the premature depletion of the pool of proliferating CTBs by favoring their differentiation.…”

“…Antibody binding was visualized using horseradish peroxidase-conjugated goat anti-rabbit secondary antibody (Invitrogen/Life Technologies), followed by autoradiography using the ECL-Western Chemiluminescence Detection Kit (GE Healthcare). Total protein load on the gel was determined by Coomassie staining, and the immunoreactive NKX3.1 protein was analyzed by scanning densitometry (ImageQuant, GE Healthcare) as described previously (25,26,33,34).…”

Review: Placental homeobox genes and their role in regulating human fetal growth

“…affected placentae compared with gestation-matched placental controls. However, homeobox genes DLX3, DLX4 and TGIF-1 showed increased expression [34,42,43] in idiopathic FGR-affected placentae compared with gestation-matched controls. Our observation of altered homeobox gene expression levels, i.e.…”

“…More specifically, we demonstrated that homeobox gene HLX is expressed primarily in proliferating cytotrophoblast cell types during early placental development [32]. We also determined the expression profile of homeobox gene DLX3 and TGIF-1 in the human placenta [33,34]. In first trimester and term placentae, DLX3 and TGIF-1 localised to the nuclei of villous cytotrophoblast cells, the syncytiotrophoblast layer and proliferating extravillous trophoblast cells in the proximal region of the invading cell columns.…”

“…We and others have identified the potential importance of homeobox genes DLX3, DLX4, GAX, ESX1L, HLX and TGIF-1 in the human placenta [27,[30][31][32][33][34]. These homeobox genes are also expressed in the embryo and play pivotal roles in embryonic development [29,35,36].…”