Abstract
ABSTRACTSignaling centers, or organizers, regulate many aspects of embryonic morphogenesis. In the mammalian molar tooth, reiterative signaling in specialized centers called enamel knots (EKs) determines tooth patterning. Preceding the primary EK, transient epithelial thickening appears, the significance of which remains debated. Using tissue confocal fluorescence imaging with laser ablation experiments, we show that this transient thickening is an earlier signaling center, the molar initiation knot (IK), that is required for the progression of tooth development. IK cell dynamics demonstrate the hallmarks of a signaling center: cell cycle exit, condensation and eventual silencing through apoptosis. IK initiation and maturation are defined by the juxtaposition of cells with high Wnt activity to Shh-expressing non-proliferating cells, the combination of which drives the growth of the tooth bud, leading to the formation of the primary EK as an independent cell cluster. Overall, the whole development of the tooth, from initiation to patterning, is driven by the iterative use of signaling centers.
Highlights
In recent years, advances in 3D and live tissue imaging have brought new understanding of the cell-level behaviors that contribute to the highly dynamic stages of morphogenesis in ectodermal organs, such as hair and teeth (Ahtiainen et al, 2014, 2016; Devenport and Fuchs, 2008; Kim et al, 2017)
A molar initiation knot is established in the placode and early bud in G1/G0 cells expressing signaling center markers Cell cycle exit is an early hallmark of ectodermal placodes (Ahtiainen et al, 2014, 2016)
The reiterative genetic regulation of tooth development via signaling centers is conserved across tooth types, but less understood is how it is interpreted into different cellular behaviors to regulate tooth shape and size
Summary
Advances in 3D and live tissue imaging have brought new understanding of the cell-level behaviors that contribute to the highly dynamic stages of morphogenesis in ectodermal organs, such as hair and teeth (Ahtiainen et al, 2014, 2016; Devenport and Fuchs, 2008; Kim et al, 2017). Morphogenesis in ectodermal organs is regulated by epithelial signaling centers, which form sequentially in specific spatiotemporal patterns and govern cell behaviors via secreted factors, including hedgehog (Hh), Wnt, fibroblast growth factor (Fgf) and bone morphogenetic protein (Bmp) family members (Dassule and McMahon, 1998; Jernvall and Thesleff, 2000; Yu and Klein, 2020). Organogenesis in teeth is initiated at embryonic day (E) with an epithelial thickening called the dental lamina. This resolves into separate domains for incisor and first molar primordia, with a toothless diastema in between. Fate-mapping studies have shown that the pEK clonally contributes to the buccal sEK, but may not contribute to the lingual counterpart (Du et al, 2017)
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