Epithelial Migration and Non-adhesive Periderm Are Required for Digit Separation during Mammalian Development

• Published in: Developmental cell 2020-03, Vol.52 (6), p.764-778.e4
• Main Authors: Kashgari, Ghaidaa, Meinecke, Lina, Gordon, William, Ruiz, Bryan, Yang, Jady, Ma, Amy Lan, Xie, Yilu, Ho, Hsiang, Plikus, Maksim V., Nie, Qing, Jester, James V., Andersen, Bogi
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement; digit separation; DNA-Binding Proteins - genetics; embryonic epidermis; Epithelial Cells - metabolism; Epithelial Cells - physiology; epithelial mechanism; Forelimb - abnormalities; Forelimb - embryology; Forelimb - metabolism; grainyhead like-3; interdigital cell death; limb development; Mice; Mice, Inbred C57BL; Morphogenesis; periderm; syndactyly; Syndactyly - genetics; Toes - abnormalities; Toes - embryology; Transcription Factors - genetics; van der Woude syndrome
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2020.01.032

The fusion of digits or toes, syndactyly, can be part of complex syndromes, including van der Woude syndrome. A subset of van der Woude cases is caused by dominant-negative mutations in the epithelial transcription factor Grainyhead like-3 (GRHL3), and Grhl3−/−mice have soft-tissue syndactyly. Although impaired interdigital cell death of mesenchymal cells causes syndactyly in multiple genetic mutants, Grhl3−/− embryos had normal interdigital cell death, suggesting alternative mechanisms for syndactyly. We found that in digit separation, the overlying epidermis forms a migrating interdigital epithelial tongue (IET) when the epithelium invaginates to separate the digits. Normally, the non-adhesive surface periderm allows the IET to bifurcate as the digits separate. In contrast, in Grhl3−/− embryos, the IET moves normally between the digits but fails to bifurcate because of abnormal adhesion of the periderm. Our study identifies epidermal developmental processes required for digit separation. [Display omitted] •Epidermal cells actively migrate into the interdigital mesenchyme•Active migration of epidermal cells is required for digit separation•Non-adhesive property of periderm cells prevents epithelial fusion between the digits•GRHL3 is required for normal periderm development and function Kashgari et al. identify an epidermal developmental process required for digit separation. During this process, epidermal cells actively migrate downward into the underlying mesenchyme, forming an interdigital epithelial tongue (IET). Fusion of the digits is prevented by the non-adhesive periderm cells on the epithelial surface.