Cytoplasmic localization of GRHL3 upon epidermal differentiation triggers cell shape change for epithelial morphogenesis

Epithelial cell shape change is a pivotal driving force for morphogenesis of complex three-dimensional architecture. However, molecular mechanisms triggering shape changes of epithelial cells in the course of growth and differentiation have not been entirely elucidated. Grhl3 plays a crucial role as a downstream transcription factor of Wnt/β-catenin in epidermal differentiation. Here, we show Grhl3 induced large, mature epidermal cells, enriched with actomyosin networks, from embryoid bodies in vitro. Such epidermal cells were apparently formed by the simultaneous activation of canonical and non-canonical Wnt signaling pathways. A nuclear transcription factor, GRHL3 is localized in the cytoplasm and cell membrane during epidermal differentiation. Subsequently, such extranuclear GRHL3 is essential for the membrane-associated expression of VANGL2 and CELSR1. Cytoplasmic GRHL3, thereby, allows epidermal cells to acquire mechanical properties for changes in epithelial cell shape. Thus, we propose that cytoplasmic localization of GRHL3 upon epidermal differentiation directly triggers epithelial morphogenesis.