ADAM10: Possible functions in enamel development

Abstract

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.

Keywords: COL17A1; RELT; ameloblasts; cell migration; cell surface proteins; enamel defects; sheddase.

FIGURE 1

Possible mechanisms by which ADAM10 may facilitate enamel development. (Top) Schematic showing how ADAM10 may cleave the ends of ameloblast cohorts so that they can slide by one another during the secretory stage of enamel development. The cell-cell connections would also be removed between the sliding cells (not shown). Black parallel lines, tight junctions; right triangles, Tomes’ processes; yellow lines, enamel rods (interrods not shown). (Bottom Left) Mouse incisor section stained red by in situ hybridization for ADAM10 (Ikeda et al., 2019). Adam10 expression begins in the apical loop and continues until the ameloblasts reach the transition stage of enamel development. Adam10 may facilitate Notch signaling to maintain the stem cell niche within the apical loop (Felszeghy et al., 2010). (Bottom Right) Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) demonstrating that pre-ameloblasts extent finger-like projections to penetrate the basement membrane (BM) that separates the pre-ameloblastss from the predentin organic matrix (Bartlett et al., 2021). Since ADAM10 is expressed during this time, it is possible that it assists in penetrating the basement membrane.

FIGURE 2

Relative expression levels of ADAM family members in murine first molar enamel organs from P5 (secretory stage) and P12 (maturation stage) mice. qPCR demonstrated that Adam8, 9, 10, 15, 17, and 19 were expressed in mouse enamel organs (Ikeda et al., 2019). However, only Adam10 was expressed predominantly in the secretory stage when ameloblast movement occurs. Three biological replicates were analyzed for each of three experiments (*, p < 0.05; **, p < 0.01; Ct, cycle threshold).