Abstract
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.
Highlights
Epithelial morphogenesis directed by multiple cellular processes, such as cell shape changes, proliferation, and migration, involves the formation of complex threedimensional architecture as seen, for example, in the formation of the mammalian neural tube[1]
Embryonic stem (ES) cell-derived embryoid bodies (EBs) consisted of central undifferentiated progenitor cells and TROMA-1 positive peripheral epidermal cells, which are formed without any additional factors (Fig. 1b)
Young’s modulus of surface ectoderm (SE) cells in Grhl3NLS/nuclear localization signal (NLS) embryos was an average of 5.796 kPa. These data indicate that SE cells expressing Grhl[3] or cytoplasmic GRHL3 (C-GRHL3) protein were stiffer than Grhl3-negative SE cells. These results suggest that Grhl[3] is essential for ensuring mechanical properties in epidermal cells against the tensile force required for epithelial morphogenesis
Summary
Epithelial morphogenesis directed by multiple cellular processes, such as cell shape changes, proliferation, and migration, involves the formation of complex threedimensional architecture as seen, for example, in the formation of the mammalian neural tube[1]. We have found that during neural tube closure the canonical Wnt signaling pathway progressively specifies SE fate at the neural plate border, where neither surface nor neural cells are specified as uncommitted ectodermal progenitors[14] These findings have led to the hypothesis that cell fate specification of SE during neurulation may be intimately linked to the epithelial morphogenesis of primary neurulation, which is governed by the non-canonical Wnt pathway involving planar cell polarity (PCP) genes[15]. GRHL3, which has been considered as a transcription factor, appears to localize in the cytoplasm upon differentiation over time to activate non-canonical Wnt signaling Such GRHL3-induced epidermal cells acquire mechanical properties necessary for cell shape change through actomyosin networks. This finding provides unique insights into the temporal mechanisms involved in the initiation of epithelial morphogenesis in coordination with cell specification during animal development
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