A Transcription Factor Feedback Loop Controls Early Placenta Development

The molecular pathways leading to development of the placenta are regulated by a feedback loop between the transcription factors Gcm1 (chorion-specific transcription factor or hGCMa), which is a mammalian homologue of the Drosophila GCM (glia cells missing) and Fzd5 (Frizzled5).

Abnormal placental development during pregnancy is associated with conditions such as preeclampsia, intrauterine growth restriction, and even fetal death in humans. Investigators at the Chinese Academy of Sciences (Beijing) worked with a mouse model of placental development that closely mimicked the process in humans. They focused on the earliest steps of placenta formation, which involves the development of the labyrinthine layer, a specialized epithelium that sits between the maternal blood and fetal blood vessels and facilitates the exchange of nutrients, gases, and wastes between the mother and fetus. Pivotal to the development of a functional labyrinth layer are the processes of folding and branching of a flat sheet of trophoblast cells (originally the outer layer of the blastocyst), and of trophoblast cell differentiation.

Results published in the April 16, 2013, online edition of the journal PLOS Biology revealed that in mice Fzd5, a receptor component of the Wnt signaling pathway, and Gcm1, an important transcription factor for labyrinth development, formed a positive feedback loop that directed normal placental development. Gcm1 up-regulated Fzd5 specifically at branching sites, and elevated Fzd5 expression in turn maintained expression of Gcm1.

Fzd5-mediated signaling was required for the disassociation of cell junctions and for the up-regulation of VEGF (vascular endothelial growth factor) expression in trophoblast cells. Furthermore, the FZD5-GCM1 signaling cascade was found to operate in primary cultures of human trophoblasts undergoing differentiation.

"We provide here genetic, molecular, pharmacological, and physiological evidence that an amplifying feedback loop between Gcm1 and Fzd5 is essential for normal placental development of mice," said senior author Dr. Haibin Wang, professor of developmental biology at the Chinese Academy of Sciences. "Besides shedding light on the fundamental mechanisms of branching morphogenesis during mouse placental development, the finding has high clinical relevance, since the Gcm1-Fzd5 signaling cascade also operates in human trophoblasts, and when its regulation goes wrong, it can be linked to trophoblast-related diseases, such as preeclampsia."

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