Gene tracking follows cells from embryo to adult

March 20, 2000

In a sense, all teeth can be considered wisdom teeth if their cells of origin are the determining factor. Scientists have developed a sophisticated genetic tracking system that allows them to follow the migration of cells as they stream from the embryonic mouse brain to the developing body, including the primordial jaw where they contribute to the formation of teeth and supporting structures. This is the first time a group of embryonic cells has been 'tagged" and followed throughout development to their final destiny. The research was a collaborative effort of several institutions, led by Dr. Yang Chai from the University of Southern California. The study, which appears in the March 21 issue of Development, was supported in part by the National Institute of Dental and Craniofacial Research.

"This technology allows us to closely follow an important group of cells that contribute not only to formation of the teeth and other craniofacial structures, but also to parts of the developing cardiovascular system," said Dr. Chai. "We will soon be able to look at animal models for a variety of human genetic disorders and observe in minute detail the effects on this key cell population. Likewise, we will be able to scrutinize corrective measures, such as gene therapy."

The cells shown by Chai and colleagues to be at the root of forming teeth, jaws, and other body parts are called neural crest, named for their site of origin. When the embryo is little more than an elongated blob, a thickened band of cells forms along the dorsal surface. This "neural plate" of cells is the future brain and spinal cord. Neural crest cells soon sprout from neural plate to form crescent-shaped bands along either side of the plate.

Traditional methods of labeling and staining cells indicate that neural crest cells leave the presumptive brain region of the embryo and migrate to distal sites of the emerging body. However, the labeling techniques have been rather imprecise until now. Dr. Chai has taken advantage of a new molecular sleight of hand to track cells by following the activity of the cells' genes.

There is a gene called Wnt1 that is only switched on in neural crest cells, making it an excellent model for a "reporter" gene. Wnt1 can be modified to produce a molecule that scientists can easily recognize as the cells move through the developing embryo. However, Wnt1 switches off before neural crest cells reach their final destination, making the cells disappear from the molecular radar screen.

The research team overcame this hurdle by modifying the Wnt1 reporter gene so that it became a switch, turning on a second reporter gene that remained active even after Wnt1 reverted to dormancy. The second gene, called ROSA26, is turned on only in cells where Wnt1 was initially active--the neural crest cells. Mice engineered with this genetic circuitry have neural crest cells that can be followed throughout development to adulthood.

Under special staining conditions, all cells of neural crest origin appear cobalt blue under the microscope, in sharp contrast to the bright pink cells originating from other embryonic tissues. This clear distinction provided the investigators with the best look yet at the cells that go into forming teeth and jaws and surrounding structures.

It was apparent that neural crest cells are key players in tooth formation, but are not the sole contributors. Cells from neural crest predominate in tissues that form internal tooth components such as dentin, pulp, and cementum--the bone-like material the forms the root. However, other cells of unknown origin were also mixed in with the neural crest, suggesting that additional instructions are needed to complete the job. The enamel layer covering the tooth crown also forms from cells other than neural crest, specifically epithelial cells that are already present in the future jaw region at the time neural crest cells move in.

In addition to tooth components, neural crest cells also contribute to non-tooth structures including facial nerves, periodontal ligament, jawbone, and the cartilaginous disc that allows the jaw to pivot in its socket. The next step, according to Chai, is to apply this technique to genetically mutated animals in order to get a better grasp of the role of neural crest cells in both normal and abnormal development of craniofacial structures and beyond.

Collaborating with Dr. Chai were Drs. Yoshihiro Ito, Pablo Bringas, Jr., Jun Han, Xaiobing Jiang, and Henry Sucov from the University of Southern California; Drs. David H. Rowitch and Andrew P. McMahon from Harvard University; and Dr. Philippe Soriano from the Fred Hutchinson Cancer Research Center in Seattle, Washington. The study was supported by the American Heart Association and the National Institute of Dental and Craniofacial Research, one of the federal National Institutes of Health, located in Bethesda, Maryland.

NIH/National Institute of Dental and Craniofacial Research

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