Polarity and the placenta.

Abstract

Placental development requires a transcription factor, grainyhead-like 2 (GRHL2), which is expressed highly in cells that help generate the branched morphology of the organ, according to a new study in mouse and human tissue [1]. Grainyhead-like transcription factors are involved in epithelial development in several species—for instance, in formation of epithelial barriers. Katharina Walentin et al. were intrigued to find that GRHL2 is also expressed at high levels in mouse basal chorionic trophoblast (BCT) cells. Those cells form an epithelial cell-like layer during early embryogenesis, with their basement membranes abutting the allantoic mesoderm, which is derived from the embryo proper. As embryogenesis proceeds, this layer of BCT cells undergoes branching in coordination with the branching of endothelial cells, and the result is proper establishment of the maternalfetal interface. To find out more, Walentin et al. generated mice deficient in Grhl2 and found major defects in BCT cell polarity and basement membrane integrity. The mice also had severe disruptions in placental branching initiated by the BCT cell layer. Molecular analyses suggested that GRHL2 positively regulates a suite of genes, including those previously implicated in placental development and epithelial morphogenesis. One of these genes is serine protease inhibitor Kunitz type 1 (Spint1), and mice deficient in Spint1 are very similar to those deficient in Grhl2. Spint1 is known to positively regulate Cdh1, encoding the cell adhesion protein E-Cadherin. The findings may have implications for human disorders such as pre-eclampsia and fetal growth retardation, which can often be traced to placental defects. The researchers found that human orthologs of GRHL2 were expressed highly in human placental cells analogous to BCT cells—human villous cytotrophoblasts. Moreover, gene targets of GRHL2 identified in previous studies showed co-regulation in human placental tissue, in particular SPINT1.