Scientists Identify Key Step in How Teeth Develop in the Womb

Investigators with Cedars-Sinai Guerin Children’s and other research institutions have identified a process responsible for the development of teeth called incisors—a discovery that could one day improve understanding of how birth defects happen.

The findings were published in Nature Cell Biology.

“By understanding how an embryo forms organs, we can start to ask questions about what goes wrong in children born with congenital malformations,” said Ophir Klein, MD, PhD, executive director of Guerin Children’s, the David and Meredith Kaplan Distinguished Chair in Children’s Health, and co-corresponding author of the study. “This work may lead to additional research into how birth defects are formed and can be prevented.”

Incisors are the sharp teeth at the front of the mouth that bite into food and cut it into smaller pieces.

Scientists know that during development, proteins called morphogens send signals to cells that coordinate tissue growth. This study showed how a signaling center—a cluster of specialized cells that regulate organ development by producing morphogens—is created.

The study is a collaboration between the laboratories of Klein at Cedars-Sinai Guerin Children’s and the University of California, San Francisco (UCSF), and professor Otger Campàs at the Physics of Life Excellence Cluster of TU Dresden in Germany and the University of California, Santa Barbara (UCSB).

“Using techniques that our lab developed to measure the mechanical changes that occur during embryonic development, we were able to understand how a pressure buildup in the tissue establishes the main signaling center of the developing tooth,” said professor Campàs, the managing director and chair of Tissue Dynamics at the Physics of Life Excellence Cluster of TU Dresden, and former associate professor of Mechanical Engineering at UCSB.

A human fetus starts to form gums at about six weeks of pregnancy. By roughly nine weeks, a fetus develops buds that will eventually sprout teeth. Investigators studied these processes in a laboratory mouse fetus, which develops similarly to a human fetus but in 21 days rather than nine months.

Investigators studied tissue samples containing the tooth bud of a laboratory mouse fetus over the period in which it develops an enamel knot, a signaling center specific to tooth formation.

The group performed several experiments to study the orientation of the cells within the tooth bud and what signals the cells send. They found the cells in the tooth bud start to grow and divide, which puts a mechanical pressure at the center of the tissue. The pressure causes the cells in the center to stop dividing and form the enamel knot.

“It’s like those toys that absorb water and grow in size,” said Neha Pincha Shroff, PhD, a postdoctoral scholar in the School of Dentistry at UCSF and co-first author of the study. “Just imagine that happening in a confined space. What happens in the incisor knot is that the cells multiply in number in a fixed space, and this causes pressure to build up at the center, which then becomes a cluster of specialized cells.”

This study builds upon the findings of another study by Klein and colleagues published in Nature Communications in 2016. The study found that a protein called YAP, which is involved in sensing mechanical signals, is required for formation of the enamel knot.

“What this latest work shows is that both mechanical pressure and molecular signaling play a role in organ development,” Klein said.

The investigators said future studies should investigate communication between molecular signals and mechanical pressure and how mechanical pressure may regulate the development of other organs.

Investigators Pengfei Xu (co-first author), Sangwoo Kim, Elijah Shelton, Ben Gross, Yucen Liu, Carlos Gomez, Qianlin Ye, Tingsheng Yu Drennon, Jimmy Hu and Jeremy Green also worked on the study.

Funding: The study was funded by the National Institute of Dental and Craniofacial Research, the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy, and Physics of Life Excellence Cluster of TU Dresden.

Read more on the Cedars-Sinai Blog: Six Questions With Ophir Klein, MD, PhD

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