New Gene May Help Scientists Understand More About How the Body Grows

CAMBRIDGE, Mass. — Scientists at the Whitehead Institute for Biomedical Research and Genetics Institute, Inc. have identified a new gene called derrière that plays a key role in the development of the frog embryo from the neck down, including the neural tube and the muscles flanking the spinal cord. Embryos lacking derrière gene function developed normal heads but only had disorganized tissue where the trunk and tail should have been. Scientists conclude that derrière controls the formation of the posterior regions of the embryo—that is, the entire body from the neck down.

These findings, published in the April issue of the journal Development (available now at www.biologists.com/development), will help scientists decipher the key genetic events involved in the development of a normal body.

"In addition, because this gene appears to play a pivotal role in inducing precursor tissues that will eventually form muscle, these studies could be useful to complement the efforts by scientists worldwide to regenerate muscle in wasting diseases," says Dr. Hazel Sive, Associate Member of the Whitehead Institute.

The derrière gene is a new member of a large family of genes called TGF-b that plays an important role in many biological functions, including development and cancer. Scientists were surprised to find a member of a familiar gene family performing an unfamiliar function— inducing normal posterior development in very early embryos—but they are also excited because the finding represents a new window into yet-unexplored aspects of development.

In the study, first author Benjamin Sun and his colleagues at the Whitehead used a yeast-based assay developed by the Cambridge-based biotech company Genetics Institute. The scientists used this assay to look for proteins secreted during the very early stages of development—in human terms, at a stage when the mother may not know she is pregnant. The scientists' goal was to find new signaling proteins that control formation of the embryo. When they found derrière active in regions known to be involved in forming the posterior of the embryo, scientists guessed that this gene would be important for posterior development.

To unravel what derrière actually does, that is, to study its function, these scientists conducted so called "gain-of-function" and "loss-of-function" experiments. In gain-of function experiments, they asked what would happen if derrière is activated in the

head region of the embryo where it is not normally active. In loss-of-function experiments, they asked what happens when derrière function is removed from the embryo altogether.

"We found that when the derrière gene is activated in the future head region of the embryo, it prevents the head from forming normally. When we activated derrière in the belly region, additional muscle and nerve tissue formed where the belly should have been," says Dr. Sive. This told scientists that the derrière gene could induce the formation of muscle and nerve tissue.

Scientists then prevented the derrière gene from functioning and found that embryos developed with normal heads but with only disorganized tissue from the neck down, including no muscle, no obvious neural tube, or tail.

"We speculate that derrière works with other key proteins to establish the formation of the body from the neck down. We plan to analyze these proteins to further study the mechanism by which derrière regulates posterior patterning," says Dr. Sun. The scientists also are looking for similar genes in zebrafish. If similar genes are found in other species, it is likely that a version of derrière exists in humans, says Dr. Sun.

Frogs and zebrafish are ideal systems for exploring the transition of a single-celled egg into a complex, multicellular organism. The development process in these animals is surprisingly similar to that in human beings, but it occurs much faster. In addition, unlike mammalian embryos, frog and zebrafish embryos are easy to obtain because they grow outside the mother&emdash;usually in a still pond, but just as readily in a petri dish.

By studying the growth and development of frog embryos in the laboratory, Dr. Sive and her associates have gained valuable information about the molecular signals that control one of the earliest stages of vertebrate development, establishment of the head-to-tail orientation. The embryonic events that Dr. Sive studies happen very early in development; in human terms, they take place within the first three weeks after conception—before most women even know they are pregnant. Finding the genes that participate in this process in all vertebrates could lead to new strategies for preventing birth defects in human beings and for repairing defects in the human nervous system.

Citation

Sun, B. I., Bush, S. M., Collins-Racie, L. A., LaVallie, E. R., DiBlasio-Smith, E. A., Wolfman, N. M., ... & Sive, H. L. (1999). derriere: a TGF-beta family member required for posterior development in Xenopus. Development, 126(7), 1467-1482.