Adam10-dependent Notch signaling establishes dental epithelial cell boundaries required for enamel formation

Thimios A Mitsiadis; Lucia Jimenez-Rojo; Anamaria Balic; Silvio Weber; Paul Saftig; Pierfrancesco Pagella

doi:10.1016/j.isci.2022.105154

Adam10-dependent Notch signaling establishes dental epithelial cell boundaries required for enamel formation

iScience. 2022 Sep 16;25(10):105154. doi: 10.1016/j.isci.2022.105154. eCollection 2022 Oct 21.

Authors

Thimios A Mitsiadis¹, Lucia Jimenez-Rojo¹, Anamaria Balic¹, Silvio Weber², Paul Saftig³, Pierfrancesco Pagella¹

Affiliations

¹ Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, University of Zurich, Plattenstrasse 11, 8032 Zurich, Switzerland.
² Miltenyi Biotec B.V. & Co. KG, 51429 Bergisch Gladbach, Germany.
³ Biochemical Institute, Christian-Albrechts-Universität Kiel, 24118 Kiel, Germany.

Abstract

The disintegrin and metalloproteinase Adam10 is a membrane-bound sheddase that regulates Notch signaling and ensures epidermal integrity. To address the function of Adam10 in the continuously growing incisors, we used Keratin14 ^Cre/+;Adam10 ^fl/fl transgenic mice, in which Adam10 is conditionally deleted in the dental epithelium. Keratin14 ^Cre/+;Adam10 ^fl/fl mice exhibited severe abnormalities, including defective enamel formation reminiscent of human enamel pathologies. Histological analyses of mutant incisors revealed absence of stratum intermedium, and severe disorganization of enamel-secreting ameloblasts. In situ hybridization and immunostaining analyses in the Keratin14 ^Cre/+;Adam10 ^fl/fl incisors showed strong Notch1 downregulation in dental epithelium and ectopic distribution of enamel-specific molecules, including ameloblastin and amelogenin. Lineage tracing studies using Notch1 ^CreERT2 ;R26 ^mT/mG mice demonstrated that loss of the stratum intermedium cells was due to their fate switch toward the ameloblast lineage. Overall, our data reveal that in the continuously growing incisors the Adam10/Notch axis controls dental epithelial cell boundaries, cell fate switch and proper enamel formation.

Keywords: Cell biology; Developmental biology; Model organism.