Master Molecule Forms Brains in Frogs and Elbows in Mice

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Alison Davis, NIGMS

The same molecule that instructs cells to meld together correctly into a healthy frog brain turns out to be a crucial factor in forming the wrists, knees, and elbows of mice, NIGMS-supported researchers at the University of California, Berkeley and their collaborators at Harvard report in the May 29 issue of Science. The function of this protein, comically dubbed Noggin, is no laughing matter--scientists are now learning that Noggin appears to perform a vital role in the proper development of tissues in organisms ranging from frogs to humans.

"I think this story illustrates particularly well how poking around in frogs can lead to something of potential health benefit," NIGMS grantee Dr. Richard Harland said.

Six years ago, Harland, a professor of molecular and cell biology at the University of California, Berkeley, and William Smith, who was then in his lab, discovered Noggin in the course of their research on the development of what might appear to be an obscure laboratory-bred organism, an African clawed frog called Xenopus laevis. Smith and Harland showed that in Xenopus embryos, Noggin performs a critical developmental function: It permits certain cells to become brain and nervous system tissue by blocking alternate pathways that might form other tissues such as skin, for instance. The protein got its name, in fact, when the team found that lab frogs formed exceptionally large heads after embryos were injected with Noggin messenger RNA (which led to the overproduction of Noggin protein).

Years ago, Harland had originally chosen to work with amphibian embryos largely because of their size and ease of surgical manipulation. Since then, that decision has paid off, yielding valuable insights into basic developmental biological mechanisms, many of which appear to prevail throughout the animal kingdom. The latest of these is revealing the important role Noggin plays in patterning the mammalian skeleton.

The potential health benefits Harland is referring to are the likely applications of his research to better understanding not just the classic "joint diseases," such as arthritis, but also a gamut of medical conditions in which there is either too much or too little bone for the body to handle, such as osteoporosis.

Harland's most recent work, in collaboration with Dr. Andrew McMahon's group at Harvard, illustrates the dramatic consequence of genetically plucking out the DNA that spells out the production of the Noggin protein from mice. Such "knockout" technology begins with snipping a gene of interest out of the chromosomes of embryonic mouse cells growing in a petri dish. The altered, "knockout" cells are then introduced into a recipient mouse, ultimately permitting researchers to breed colonies of mice "free" of the particular gene of study and then to observe how the mice fare without it.

 Noggin Image

Noggin-less mouse embryos (left photo) have no joints (stained blue in normal mouse embryos, right photo). In creating Noggin knockout mice, Harland and co-workers inserted a dummy gene in its place (stained red, thus indicating where the Noggin protein would normally be located).

In the case of the Noggin knockout mice, the answer is: not too well. In fact, mice missing the Noggin gene don't survive until birth. But analyzing the unborn embryos before they died turned up several interesting results. The researchers found that mice lacking the Noggin protein possessed severe skeletal defects, not the least of which was the complete absence of limb joints. Instead of having an elbow, for instance, the mutant mice had one long, unsegmented arm. The mice's fingers and toes also had no joints and, in addition, exhibited occasional spurs in the cartilage that makes up such tissues.

In addition to the likely clinical implications of the work, of particular interest to scientists is the way Noggin influences joint formation (and probably all of its physiological roles in different organisms). What happens in the absence of Noggin, Harland surmises, is that the future joints of mouse limbs are overtaken by growth factors called bone morphogenetic proteins, or BMPs, which promote the growth of bone. The result is increased cartilage and bone deposition and no joint formation.

In other words, Harland and his colleagues conclude, Noggin appears to do its job by keeping the activity of other cellular growth factors in check. Noggin thus permits what developmental biologists call a "default fate" to proceed as the body intended, resulting in the formation of the appropriate tissue in the appropriate place.

In particular, Noggin appears to control the activity of BMPs. Much like a sculptor would carve a block into a hand full of fingers, a molecular chisel (as yet unidentified) cuts the coarsely drawn skeleton into its final form. If there is too much BMP activity, according to Harland, that carving simply doesn't occur. Noggin prevents an excess of BMP action throughout the skeleton, and in the joints, he added, "allows the sculptor to get to work."

Companies are already interested in the potential applications of the basic research on Noggin's role in choreographing skeletal development. Regeneron Pharmaceuticals of Tarrytown, New York, is actively investigating whether Noggin-like compounds that block BMPs might help stunt bone growth in hip replacement patients as well as in some patients with osteosarcoma, a type of bone cancer.

This research was supported by grants from the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health that supports basic biomedical research, and the American Cancer Society.


Brunet LJ, McMahon JA, McMahon AP, Harland RM. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 1998;280:1455-7.

Zimmerman LB, De Jesus-Escobar JM, Harland RM. The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell 1996;86:599-606.

Smith WC, Harland RM. Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 1992;70:829-40.

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