image: Proposed model of early molar patterning in mice. In normal development (top), the blue molar-forming region on one side of the first pharyngeal arch separates into upper- and lower-jaw domains as the maxillary prominence develops. In the jaw-fusion model with excess BMP4 in cranial neural crest cells (bottom), migration and separation are impaired. E denotes embryonic day; red arrows indicate the proposed direction of cell movement. This is a schematic model, not an image of a mature tooth splitting. Cropped from panel Z of the authors' supplied composite image, corresponding to Figure 2Z of the paper; scientific content is unchanged.
Credit: ©Science China Press
Before tooth germs are anatomically discernible, how does an embryo set aside separate places for the upper and lower molars? A study in mice traced the answer back to an earlier stage: in the developing face, each side initially has only one common molar-forming region, and then it is divided into upper- and lower-jaw domains.
Published in Science China Life Sciences, the research brings an earlier step in tooth development into focus. It also offers a possible developmental explanation for missing molars associated with syngnathia, a rare condition in which the upper and lower jawbones are fused at birth.
The international team includes researchers from Fujian Normal University, King's College London, the Czech Academy of Sciences and Tulane University. Rather than starting with a recognizable tooth bud, they examined the earlier events that establish how molars form.
In mouse embryos, separate upper and lower molar germs, the developing structures that will form molar teeth, are recognizable by embryonic day 11.5 (E11.5). But their earlier origins have been unclear. Do they begin independently, or emerge from a common precursor region?
The team combined gene-expression mapping, genetic lineage tracing and tissue transplantation to investigate. Their findings support a two-step model: a common molar primordium, or earliest molar-forming region, is present on each side by E9.0, then separates into upper and lower domains around E9.5 to E9.75.
Genetic labeling followed early cells expressing the gene Fgf8 in the surface tissue of the first pharyngeal arch, an embryonic structure that contributes to the jaws. Descendants of these cells contributed to both upper and lower molar germs. In a complementary test, tissue from one side of the arch was transplanted beneath a mouse kidney capsule, where it could continue developing. E9.0 grafts formed one molar, whereas E10.0 grafts formed two, supporting the proposed transition from a shared primordium to separate molar-forming domains.
A jaw-fusion model helped reveal what can go wrong. The researchers studied mice engineered to produce excess BMP4, a developmental signaling protein, in cranial neural crest cells. These cells supply much of the face's skeletal and connective tissue. Instead of separate upper and lower molar germs, the mutants developed a single misplaced molar germ on each side at the junction of the fused jaws.
Fluorescent dye tracking linked this defect to cell movement within the developing jaw region. In normal embryos, labeled neural crest-derived cells moved away from the junction toward both the upper and lower jaw regions. In mutants, they largely remained near the labeling site. At this early stage, cell proliferation and cell death did not differ significantly between the groups, pointing to disrupted movement rather than too few cells.
Molecular analyses implicated a disturbed gene-regulatory network involving BMP4 and FGF8, together with excessive activity of p38, a signaling pathway inside cells. This connects the shared-origin model to a broader developmental question: how molecular signals coordinate cell movements to establish distinct organ-forming regions.
The team then tested the p38 inhibitor SB203580 during embryonic development. The treatment restored separate upper and lower molar germs in six of nine treated mutants, but jawbone fusion persisted in all nine. The contrast suggests that the dental and jaw bone abnormalities can be separated mechanistically, rather than one being an inevitable consequence of the other.
The findings offer a framework for investigating why jaw fusion and missing molars can occur together in people. However, this is an animal study, and the small drug-intervention experiment is not evidence of a treatment for human syngnathia or missing teeth. Whether the same early separation process and molecular disruption occur in humans remains to be established.
The work shifts attention to a stage before recognizable tooth germs appear: establishing separate places for teeth to develop. Understanding tooth formation therefore requires asking not only how a tooth grows, but how its future position is laid out.
Chensheng Lin is the first author and a corresponding author; Jeremy B. A. Green and Xuefeng Hu are co-corresponding authors. The work was supported by the National Natural Science Foundation of China and a King's College London-KC Wong Postdoctoral Fellowship, with research infrastructure support for the Czech Centre for Phenogenomics.
Journal
Science China Life Sciences
Method of Research
Experimental study