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ADAM10 is a multi-functional proteinase that can cleave approximately 100 different substrates. Previously, it was demonstrated that ADAM10 is expressed by ameloblasts, which are required for enamel formation. The goal of this study was to determine if ADAM10 is necessary for enamel development. Deletion of Adam10 in mice is embryonically lethal and deletion of Adam10 from epithelia is perinatally lethal. We therefore deleted Adam10 from ameloblasts. Ameloblast-specific expression of the Tg( Amelx -i Cre )872pap construct was confirmed. These mice were crossed with Adam10 floxed mice to generate Amelx- i Cre ; Adam10 fl/fl mice ( Adam10 cKO). The Adam10 cKO mice had discolored teeth with softer than normal enamel. Notably, the Adam10 cKO enamel density and volume were significantly reduced in both incisors and molars. Moreover, the incisor enamel rod pattern became progressively more disorganized, moving from the DEJ to the outer enamel surface, and this disorganized rod structure created gaps and S-shaped rods. ADAM10 cleaves proteins essential for cell signaling and for enamel formation such as RELT and COL17A1. ADAM10 also cleaves cell-cell contacts such as E- and N-cadherins that may support ameloblast movement necessary for normal rod patterns. This study shows, for the first time, that ADAM10 expressed by ameloblasts is essential for proper enamel formation.

ADAM10 is A Disintegrin And Metalloproteinase (ADAM) family member that is membrane bound with its catalytic domain present on the cell surface. It is a sheddase that cleaves anchored cell surface proteins to shed them from the cell surface. ADAM10 can cleave at least a hundred different proteins and is expressed in most tissues of the body. ADAM10 is best characterized for its role in Notch signaling. Interestingly, ADAM10 is transported to specific sites on the cell surface by six different tetraspanins. Although the mechanism is not clear, tetraspanins can regulate ADAM10 substrate specificity, which likely contributes to the diversity of ADAM10 substrates. In developing mouse teeth, ADAM10 is expressed in the stem cell niche and subsequently in pre-ameloblasts and then secretory stage ameloblasts. However, once ameloblasts begin transitioning into the maturation stage, ADAM10 expression abruptly ceases. This is exactly when ameloblasts stop their movement that extends enamel crystallites and when the enamel layer reaches its full thickness. ADAM10 may play an important role in enamel development. ADAM10 can cleave cadherins and other cell-cell junctions at specific sites where the tetraspanins have transported it and this may promote cell movement. ADAM10 can also cleave the transmembrane proteins COL17A1 and RELT. When either COL17A1 or RELT are mutated, malformed enamel may occur in humans and mice. So, ADAM10 may also regulate these proteins that are necessary for proper enamel development. This mini review will highlight ADAM10 function, how that function is regulated by tetraspanins, and how ADAM10 may promote enamel formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shahid, Ikeda, Layana and Bartlett.)