Biologists Find Gene Network That Gave Rise To First Tooth

The researchers say their finding lays out a core evolutionary list of molecules needed to make a tooth. These original dental genes, like a four-cylinder Model T engine to the marvels of modern automotive engineering, were then gradually replaced, rewired, or left in place to produce the various shapes and sizes of teeth now found in nature, from shark to mouse to monkey to human.

Todd Streelman, Ph.D., a scientist at Georgia Institute of Technology in Atlanta and senior author on the study, said the discovery should provide useful information for researchers attempting to coax diseased teeth back to health with biology rather than the traditional hand-held drill. "To truly understand any part of the body, you must know how it was originally designed," said Streelman. "This is especially important when it comes to teeth. The teeth of fishes not only develop distinct sizes and shapes, they are also repaired, shed, and replaced throughout life."

"But these characteristics, once intertwined, have been decoupled through the ages in higher organisms, and the ability to repair and regrow teeth has been largely lost," he added. "If we could learn to selectively restore these traits in the dentist's office, it would mark a major step forward in helping people protect and repair their teeth. I think this gene network provides a nice evolutionary clue on how best to proceed."

Teeth are extremely ancient structures that arose in early vertebrates - animals with a backbone - but interestingly predate jaws. The fossil record indicates the first patterned set of teeth, or dentition, arose in the back of the pharynx of jawless fish. The pharynx is a tube-like part of the throat that functioned in early fish as a rudimentary jaw in which pharyngeal teeth filtered and processed food.

Over the millennia, as vertebrates developed more powerful opposing jaws for feeding in water and on land, most species adapted their dentitions there. Today, scientists can offer a real-life glimpse of this developmental bifurcation by pointing to vertebrates, such as zebrafish, that retain pharyngeal teeth only; others, such as mouse and human, that have oral teeth only; and a subset, including cichlids, that thrives with both.

That's where the cichlids enter the research picture. In Lake Malawi, one of East Africa's Great Lakes, scientists can find a great diversity of dentitions among more than 1,000 cichlid species. Most species are endemic to East Africa and closely related, but they have evolved into a rainbow of colors, shapes, and sizes over the last one to two million years to enable them to inhabit the lake's diverse terrain.

"They really are quite unique," said Gareth Fraser, a postdoctoral fellow in the Streelman laboratory and lead author on the paper. "Some cichlids have in total more than 3,000 teeth lining their pharynx and mouth. Each tooth gets replaced every 50 to 100 days with each tooth position maintaining its own stem cell niche, or environment, that initiates development of the next generation of teeth."

Last year, Fraser and colleagues described a gene network that seemed to control the patterning of tooth size, number, and spacing in Lake Malawi cichlids. Interestingly, the genes began this patterning very early in embryonic development. This indicated to the scientists that teeth are patterned similarly to other ectodermally-derived organs, such as feathers and hairs. The ectoderm is one of three germ layers, or groups of cells, that form the external covering of a developing embryo.

They then asked a follow-up question: Is tooth number controlled similarly in the pharyngeal and oral jaw? As straightforward as the question seemed, it made no obvious biological sense. The two jaws are developmentally decoupled, as separate and distinct spatially in the embryo as Africa and North America. What's more, the oral jaw is a relative evolutionary newcomer that is thought to have originated from the loss of a particular set of genes during the transition from jawless to jawed vertebrates.

As described in their current PLoS Biology paper, co-author Darrin Hulsey, Ph.D., now at the University of Tennessee, found tooth number was indeed correlated in the two jaws. This surprising finding then raised the all-important question of how this was developmentally possible.

The scientists hypothesized that their previously described gene network might hold the key. The term "network" is used here to connote multiple genes that broadly synchronize their expression during a phase of development, not in the systems biology sense of nodes of direct temporal interaction.

Their hunch turned out to be correct. "We found that even though these two jaws are evolutionarily and developmentally distinct, they share a network of genes that pattern and limit tooth number," said Fraser. "What's really interesting is this network includes genes that are known to be involved in the patterning of hairs, feathers, and other ectodermally-derived tissues. This tells us that the network is quite ancient and fundamentally important to creating a dentition; otherwise, it would have been lost in time between the evolution of the two jaws."

"Our work also shows the power of evolutionary models like cichlids in biomedical research," added Streelman. "You don't need to artificially turn genes on or off under controlled laboratory conditions to see what might happen. The cichlids are nature's own experiment, and they open up exciting biological opportunities that you just can't glean as possibilities from traditional model organisms."

The National Institute of Dental and Craniofacial Research (NIDCR) is the Nation's leading funder of research on oral, dental, and craniofacial health.