Stephen J. Renaud Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 5C1, Canada; Children's Health Research Institute, Lawson Health Research Institute, London, Ontario N6A 5C1, Canada Corresponding author: srenaud4uwo.ca Abstract

In the human placenta, cell fusion is crucial for forming the syncytiotrophoblast, a multinucleated giant cell essential for maintaining pregnancy and ensuring fetal health. The formation of the syncytiotrophoblast is catalyzed by the evolutionarily modern fusogens syncytin-1 and syncytin-2. In this issue of Genes & Development, Esbin and colleagues (doi:10.1101/gad.351633.124) reveal a critical role for the transcription factor TFEB in the regulation of syncytin expression and the promotion of trophoblast fusion. Notably, TFEB's pro-fusion role operates independently of its well-known functions in lysosome biogenesis and autophagy, suggesting that TFEB has acquired additional functions to promote cell fusion in the human placenta.