Cleft palate (CP), one of the most common congenital diseases, arises from failures in secondary palatogenesis during embryonic development. Several human genetic syndromes featuring CP and ectodermal dysplasia have been linked to mutations in genes regulating cell-cell adhesion, yet mouse models have largely failed to recapitulate these findings. Here, we utilize in utero lentiviral-mediated genetic approaches in mice to provide the first direct evidence that the nectin-afadin axis is essential for proper palate shelf elevation and fusion. Using this technique, we demonstrate that palatal epithelial conditional loss of afadin (Afdn)—an obligate nectin- and actin-binding protein—induces a high penetrance of CP, not observed when Afdn is targeted later using Krt14-Cre. We implicate Nectin1 and Nectin4 as critical players, since loss of either induces a low penetrance of mild palate closure defects, while loss of both causes severe CP with a frequency similar to Afdn loss. Finally, expression of the human disease mutant NECTIN1W185X causes CP with greater penetrance than Nectin1 loss, suggesting this alteration may drive CP via a dominant interfering mechanism.
Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1
Present address: Molecular and Cellular Biology Program, University of California, Berkeley, Berkeley, CA, USA
Present address: Department of Genetics, Stanford University, Palo Alto, CA, USA
Currently Viewing Accepted Manuscript - Newer Version Available
Kendall J. Lough, Danielle C. Spitzer, Abby J. Bergman, Jessica J. Wu, Kevin M. Byrd, Scott E. Williams; Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1. Development 2020; dev.189241. doi: https://doi.org/10.1242/dev.189241
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