How Embryonic Proteins Determine Body Axis

Getting Organized: How Embryonic Proteins Determine Body Axis
Release Date:
4/30/1997
Contact:
Doris Brody, NIGMS

In the beginning, developing embryos look very much alike. But what determines the subsequent course of events? Will an embryo become a fly or a human, a frog or a katydid? How will the developing cells differentiate into specialized cells like nerve and muscle? For the last several years, scientists have been closing in on the specific molecular pathways that determine developmental fate. One focus of their attention is a tiny bit of embryonic tissue called the Spemann organizer. Over 70 years ago, German scientists Hans Spemann and Hilde Mangold showed that transplantation of the "organizer" region from the dorsal (back) side of one amphibian embryo to the ventral (belly) side of another caused cells in the belly of the recipient embryo to differentiate as if they were on the back of the embryo, leading to the development of an amphibian embryo with two heads and two spinal cords.

For many years, scientists sought to identify the molecules produced by the organizer that could have such an amazing effect on embryonic development. The first such protein, Noggin, was identified in 1992 by NIGMS grantee Richard Harland, Ph.D., and his colleagues at the University of California, Berkeley. This protein is secreted from the cells of the organizer and promotes dorsal (which is normal for frogs) cell fates in the frog embryo. Thus, Noggin is a key molecule in the cascade of events that organizes the dorsal-ventral (back to belly) axis of the embryo. However, it remained unclear exactly how Noggin functioned.

Now, work from two labs, Dr. Harland's and that of another NIGMS grantee, Edwin Ferguson, Ph.D., at the University of Chicago, has shown that Noggin works by binding to and interfering with the activity of another secreted protein, called BMP-4. Since BMP-4 promotes ventral fates in the embryo, this work indicates that Noggin promotes dorsal fates by interfering with the BMP-4 signal. The implication of these findings is that developing frog (and probably all vertebrate) embryos secrete a molecular signal that causes cells to organize on a ventral axis, and that this signal must be blocked in the dorsal regions of the embryo to allow for the normal development of the brain and spinal cord.

Dr. Harland performed his work in frogs. However, Dr. Ferguson used fruit flies in his experiments. Dr. Ferguson had previously shown that a protein very similar to BMP-4, called Dpp, promotes dorsal (which is not normal for fruit flies) development in fruit flies. In his recent work, Dr. Ferguson showed that Noggin could block the action of the Dpp protein, leading to the development of a ventral axis in fruit fly embryos.

If Dr. Ferguson's results sound a bit topsy-turvy, it is because they are. Insects can be thought of as upside-down vertebrates: While the central nervous system of a vertebrate is on its dorsal side, the central nervous system of an insect is on its ventral side. The findings from Dr. Ferguson's lab provide a molecular basis for understanding a prediction made over 170 years ago by a French zoologist, E. Geoffroy-St.-Hilaire, who said that the same body plan existed in both vertebrates and insects, but that there had been an inversion of the dorsal-ventral axis since the evolutionary divergence of the two groups of animals.

This knowledge will be very useful to researchers who study early development in animal models, with the eventual goal of understanding human development. In addition, both Noggin and Dpp are members of an extremely important protein family called transforming growth factor betas. These proteins regulate many processes, including cell proliferation and tissue repair--thus this work adds critical information needed for advances in understanding many diseases, including cancer.

REFERENCES

Holley S, Neul J, Attisano L, Wrana J, Sasai Y, O'Connor M, De Robertis E, Ferguson E. The Xenopus Dorsalizing Factor Noggin Ventralizes Drosophila Embryos by Blocking Dpp Signaling Upstream of Receptor Activation. Cell 1996;86:607-17.

Zimmerman L, De Jesus-Escobar J, Harland R. The Spemann Organizer Signal Noggin Binds and Inactivates Bone Morphogenetic Protein-4. Cell 1996;86:599-606.

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