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

2020; Elsevier BV; Volume: 52; Issue: 6 Linguagem: Inglês

10.1016/j.devcel.2020.01.032

1878-1551

Ghaidaa Kashgari, Lina Meinecke, William Gordon, Bryan Ruiz, Jady Yang, Amy Lan, Yilu Xie, Hsiang Ho, Maksim V. Plikus, Qing Nie, James V. Jester, Bogi Andersen,

Congenital limb and hand anomalies

Highlights•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 functionSummaryThe 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.Graphical abstract