The Forces that Sculpt a Tooth
Cells in the jaw are literally squeezed into becoming command centers that direct tooth formation
In Brief:
- Multiplying cells create pressure that triggers the formation of command centers that direct tooth formation in mice growing in the womb.
- Understanding how a tooth develops may offer insights into how diseases arise in newborns and how to rebuild damaged tissues and organs.
How does a tooth grow from scratch? Scientists have been pondering this question for decades. What they do know is that balls of cells known as enamel knots form in the developing embryo and command nearby cells to organize into teeth. But scientists have had very little insight into how these knots emerge — until recently.
Pressure created by multiplying cells appears to physically squeeze enamel knots into existence, according to a study published in Nature Cell Biology. The findings, partly supported by NIDCR, may offer general clues into how organs develop and how glitches in this process can lead to disorders at birth. Unravelling the basic workings of tooth development may also pave the way for using tissue engineering to repair teeth and regrow other organs.
"The biggest takeaway is that there's an entire world of physical forces out there involved in forming an organism’s tissues and organs," said developmental biologist and co-lead author Ophir Klein, M.D., Ph.D., of the University of California, San Francisco and Cedars-Sinai Medical Center. "We think so much about genetics and molecular signaling as being the basis for development, and while that's really important, there's this whole other level of properties that impact the structure of the cells and how they interact."
A Hypothesis Forms
About a decade ago, the unique arrangement of enamel knot cells led to discussions between Dr. Klein and biophysicist and co-lead author Otger Campàs, Ph.D., of Technische Universität in Dresden, Germany. To Dr. Campàs, the geometry of the knot — a ring of oval-shaped, elongated cells surrounding a bundle of cells at the center — suggested that physical forces may help form the structure.
To study enamel knot formation, the team examined clusters of cells in the developing mouse jaw called tooth buds, which later sprout into teeth. Enamel knots form within tooth buds. By injecting oil droplets into the bud, the researchers could measure shifts in pressure based on how the droplets bent.
As cells multiplied in the fixed space of the bud, pressure built up most on the cells at the center of the cluster. As a result, these cells stopped growing and formed the enamel knot. When the team blocked cell multiplication in the tooth bud, there was a lack of pressure, and the enamel knot failed to form. When the scientists artificially added pressure to the tissue, the enamel knot again emerged. The results suggest that physical force is necessary for enamel knot formation.
How Do Cells Sense Force?
This raised another question: How do the cells sense force in the first place? To find out, the team turned to a force-sensing protein called YAP, known to be essential for enamel knot development. Depending on how a cell is stretched and squished, YAP moves in and out of the cell’s DNA storage center, called the nucleus. In the nucleus, YAP helps drive cell growth, but outside of the nucleus, the YAP protein typically remains inactive.
The researchers color-tagged YAP, tracking its location during knot formation. They found that the outer layer of cells that were under less pressure had more YAP in their nucleus, which drove their growth. In contrast, in the core of the enamel knot, where cells are under high pressure, most YAP stayed outside of the nucleus, remaining inactive. This likely halted the cells’ growth, enabling formation of the enamel knot. The findings suggest that YAP appears to guide the cells' responses to physical forces.
In the future, the researchers plan to study the molecular events that follow the YAP response. They want to investigate how physical force, genes, and molecules work together to shape organ development.
“Our study shows a role for mechanics in organ development that wasn’t previously appreciated,” said Dr. Klein. “Everything we learn about how organs develop can help us think about how we can one day use this knowledge to build or repair organs.”
Related Links
Reference
- Shroff NP, Xu P, Kim S, Shelton ER, Gross BJ, Liu Y, et al. Proliferation-driven mechanical compression induces signalling centre formation during mammalian organ development. Nat Cell Biol. 2024 Apr;26(4):519-529. doi: 10.1038/s41556-024-01380-4. Epub 2024 Apr 3.
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February 2025