Disruption of the nectin-afadin complex recapitulates features of the human cleft lip/palate syndrome CLPED1.
Cleft palate (CP), one of the most common congenital conditions, 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 use 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 being crucially involved, as 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 NECTIN1 causes CP with greater penetrance than Nectin1 loss, suggesting this alteration may drive CP via a dominant interfering mechanism.
['Lough|Kendall J|KJ|0000-0001-9663-6983', 'Spitzer|Danielle C|DC|0000-0003-4827-1857', 'Bergman|Abby J|AJ|', 'Wu|Jessica J|JJ|', 'Byrd|Kevin M|KM|', 'Williams|Scott E|SE|0000-0001-9975-7334']
D000818:Animals D002971:Cleft Lip D002972:Cleft Palate D004847:Epithelial Cells D006801:Humans D019426:Integrases D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D008840:Microfilament Proteins D009154:Mutation D000075983:Nectins D038081:Organogenesis D010159:Palate D019683:Penetrance D013577:Syndrome
CLPED1 Cleft palate Palatogenesis Afadin Nectin