Regrow a tooth? Fish, yes! Humans, maybe ...

When a Lake Malawi cichlid loses a tooth, a new one drops neatly into place as a replacement. Why can't we humans regrow our teeth lost to injury or disease?

Working with hundreds of these colorful fish, researchers are beginning to understand how cichlids produce hundreds of teeth throughout their adult life. By understanding how tissues in embryonic cichlids become either teeth or taste buds, researchers hope to some day regenerate teeth in humans. Like other mammals, we only get two sets (baby and adult) to last our lifetime.

The research was conducted by scientists from Georgia Institute of Technology in Atlanta, Georgia, and King's College in London, United Kingdom. It was published October 19 in an early edition of the journal Proceedings of the National Academy of Sciences or PNAS. The research was supported by the National Institute of Dental and Craniofacial Research, which is part of the U.S. National Institutes of Health.

"We have uncovered developmental plasticity between teeth and taste buds, and we are trying to understand the pathways that determine the fate of cells toward either dental or sensory development.

Jeffrey Todd Streelman PhD, Professor and Associate Chair for Graduate Studies, Georgia Tech School of Biology

Worldwide, nearly 60 percent of people have lost all their teeth by the time they reach the age of 60. Beyond the painful dental health issues, tooth loss can causes significant medical and nutritional problems that can shorten life.

To understand more about pathways that lead to the growth and development of teeth, Streelman and first author Ryan Bloomquist - a DMD/PhD student at Georgia Tech and Georgia Regents University - studied how teeth and taste buds grow. Both structures eminate from the same epithelial tissue in embryonic fish. Unlike humans, fish have no tongues, so their taste buds are mixed in with their teeth, sometimes in adjacent rows located along the jaw.

The Lake Malawi cichlids have adapted their teeth and taste buds to thrive in their unique living conditions. One species eats plankton and needs few teeth because it visually locates food and swallows it whole. Another species lives by scraping algae from rocky lake formations. This requires both more teeth and more taste buds to distinguish its food. Researchers crossed the two closely-related species, and in a second generation of these hybrids, saw substantial variation in the numbers of teeth and taste buds. By studying genetic deviation in some 300 of these second-generation hybrids, they found how to tease out genetic components causing teeth and taste bud variation.

Streelman explains:  "We were able to map regions of their genomes that correlated to the densities of each of these [two] structures. And through a collaboration with colleagues at King's College in London, we were able to demonstrate that in mice, a few poorly studied genes were also involved in the development of teeth and taste buds."

By bathing embryonic fish in chemicals which influenced pathways involved in tooth and taste bud formation, researchers boosted the growth of taste buds at the expense of teeth. They had learned how to manipulated development of either structure.

Epithelial cell changes begin five to six days after fish eggs are fertilized, at a stage when embryonic fish have eyes and a brain - but are still growing jaws.

"There appear to be molecular switches that will shift the fate of the common epithelial cell to either dental or sensory structure," Streelman adds.

Though having very different purposes and anatomy, teeth and taste buds originate from the same epithelial tissue within the developing jaws of embryonic fish. These tiny buds differentiate later into soft taste buds or teeth with hard enamel.

Streelman: "It's not until late in the development of a tooth that enamel and dentine form. In the earliest stages, these structures are really very similar."

Studies in fish and mice suggest the possibility that with the right molecular signals, epithelial tissue in humans might also regenerate new teeth.

"It was not previously thought that development would be so plastic for structures that are so different in adult fish," Streelman said. "Ultimately, this suggests that the epithelium in a human's mouth might also be more plastic than we previously thought. The direction our research is taking in terms of human health, is to figure out how to coax the epithelium to form one structure or the other."

But growing new teeth won't be enough, Streelman cautions, we also need to understand how nerves and blood vessels grow inside a tooth.

"The exciting aspect of this research is being able to identify genes and genetic pathways directing tooth and taste bud development in fish, and then study these in mammals. The more we understand basic biology in natural processes, the more we can develop the next generation of clinical therapies. In this case, how to biologically regenerate replacement teeth."

Paul Sharpe PhD, Professor, King's College, and co-author.

Streelman and research technician Teresa Fowler are now working to determine how far into cichlid adulthood plasticity between teeth and taste buds extends, and how to trigger such a change.

Abstract
Significance -Teeth and taste buds are placode-derived organs studied in isolation because of their separate anatomical locations in mammals. Yet, the mouth and pharynx of many aquatic vertebrates, including bony fishes, are lined with teeth and taste buds, one next to the other. Using a combination of genome mapping, synexpression analysis, and small-molecule manipulation, we identify factors that couple tooth and taste bud density (Wingless signals) and those that differentiate the identity of each organ from a common epithelial lamina (BMP, Hedgehog). Integrating results from fishes and mouse suggests a model wherein the regulatory hierarchies that configure teeth and taste buds on mammalian jaws and tongues may be evolutionary remnants inherited from ancestors whose oral organs were copatterned from common epithelium.

Abstract
Teeth and taste buds are iteratively patterned structures that line the oro-pharynx of vertebrates. Biologists do not fully understand how teeth and taste buds develop from undifferentiated epithelium or how variation in organ density is regulated. These organs are typically studied independently because of their separate anatomical location in mammals: teeth on the jaw margin and taste buds on the tongue. However, in many aquatic animals like bony fishes, teeth and taste buds are colocalized one next to the other. Using genetic mapping in cichlid fishes, we identified shared loci controlling a positive correlation between tooth and taste bud densities. Genome intervals contained candidate genes expressed in tooth and taste bud fields. sfrp5 and bmper, notable for roles in Wingless (Wnt) and bone morphogenetic protein (BMP) signaling, were differentially expressed across cichlid species with divergent tooth and taste bud density, and were expressed in the development of both organs in mice. Synexpression analysis and chemical manipulation of Wnt, BMP, and Hedgehog (Hh) pathways suggest that a common cichlid oral lamina is competent to form teeth or taste buds. Wnt signaling couples tooth and taste bud density and BMP and Hh mediate distinct organ identity. Synthesizing data from fish and mouse, we suggest that the Wnt-BMP-Hh regulatory hierarchy that configures teeth and taste buds on mammalian jaws and tongues may be an evolutionary remnant inherited from ancestors wherein these organs were copatterned from common epithelium.

In addition to those already mentioned, the research included Nicholas Parnell and Kristine Phillips from Georgia Tech, and Tian Yu from King's College.

This research is supported by the National Institute of Dental and Craniofacial Research, part of the U.S. National Institutes of Health, under grants 2R01DE019637 (to J.T.S.) and 5F30DE023013 (to R.F.B.). Any opinions or conclusions are those of the authors and may not necessarily represent the official views of the NIH.

CITATION: Ryan F. Bloomquist, et al., "Co-Evolutionary Patterning of Teeth and Taste Buds," (Proceedings of the National Academy of Sciences, 2015).

Return to top of page

Oct 21, 2015   Fetal Timeline   Maternal Timeline   News   News Archive   

Male Malawi cichlid
Image Credit: Ashley Kirk