In a breakthrough discovery, scientists have found that a system of opposing genetic forces determines why mammals develop a single row of teeth, while sharks sport several.
The study suggests that carefully understanding the genetic program may prove helpful for scientists to re-grow missing teeth and prevent cleft palate, one of the most common birth defects.
Gene expression is the process by which information stored in genes is converted into proteins that make up the body's structures, and carry its messages.
And gene expression determines the development of teeth and palate while the baby's face takes shape in the womb. Related abnormalities lead to the development of teeth outside of the normal row, missing teeth and cleft palate, and the new insights suggest ways to combat these malformations.
In the new study, it was found that turning off a single gene in mice resulted in development of extra teeth, next to and inside of their first molars.
"This finding was exciting because extra teeth developed from tissue that normally does not give rise to teeth," said Dr. Rulang Jiang, associate professor of Biomedical Genetics in the Center for Oral Biology at the University of Rochester Medical Center.
He added: "It takes the concerted actions of hundreds of genes to build a tooth, so it was amazing to find that deleting one gene caused the activation of a complete tooth developmental program outside of the normal tooth row in those mice. Finding out how the extra teeth developed will reveal how nature makes a tooth from scratch, which will guide tooth regeneration research."
In the current study, Jiang and colleagues generated mice that lacked the oddskipped related-2 (Osr2) gene, which encodes one of many transcription factors that turn genes on or off.
"Knocking out" (deleting) the Osr2 gene resulted in cleft palate, a birth defect where the two halves of the roof of the mouth fail to join up properly, leaving a gap.
Secondly, and surprisingly, the Osr2 "knockout" mice developed teeth outside of the normal tooth row.
Jiang decided to focus his research first on the effect of Osr2 on teeth patterning (vs. cleft palate) because much more was known at the time about teeth development pathways.
Earlier studies have shown that bone morphogenic protein 4 (BMP4) is an important factor for the initiation of teeth, and that a protein called Msx1 amplifies the BMP4 tooth-generating signal.
The researchers suggested for the first time that some unknown factor was restricting the growth of teeth into one row by opposing the Bmp4 signal.
The current study provides the first solid proof that the precise space where mammals can develop teeth (the "tooth morphogenetic field") is shaped and restricted by the effect of Osr2 on the expression of the Bmp4 gene within the mesenchymal cell layer.
The researchers demonstrated that removing the Osr2 gene results in extra teeth outside of the normal row.
Osr2 restricts Bmp4 expression to the tooth mesenchyme under the dental lamina, and in Osr2's absence, Bmp4 gene expression expands into the jaw mesenchyme outside of the tooth row.
A second major finding of the study backs up another emerging theory which holds that careful regulation of competing pro- and anti-tooth initiation signals controls how mammalian teeth come one by one in sequence.
As each tooth develops, something must prevent it from forming too close to the next or mammals would have no gaps between their teeth. When this mechanism occasionally falters, adjacent teeth come in fused together.
Since evolution is not perfect, wisdom teeth (third molars) often come in too close to their predecessors, and must be pulled to make space.
The researchers claimed that BMP4 cooperates with other factors to create a temporary zone around each tooth where no other tooth can grow.
When the tooth gets closer to maturity, Msx1 overwhelms decreasing levels of inhibitory factors to start the BMP4-driven development of the next tooth.
Since the jaw is growing at the same time teeth are forming, it follows that each tooth must also receive signals that enough jaw has grown in for the next tooth to start forming atop it.
The study has been published in the journal Science.