Researchers Discover Promoter of Nerve Tissue in Frogs

Findings might one day lead to a way to regenerate brain cells for humans

Researchers at The Rockefeller University have discovered that a protein known to be involved in the early development of embryos indirectly leads to the formation of nerve tissue in frogs. The findings, reported in the March 22 issue of Nature, may have applications in such neurodegenerative diseases as Alzheimer’s and Parkinson’s.

Ali Hemmati Brivanlou

Rockefeller University Professor Ali Hemmati Brivanlou, head of the Laboratory of Molecular Vertebrate Embryology, and Chenbei Chang, a Rockefeller research associate, in collaboration with scientists at Millennium Pharmaceuticals, show that a protein found in the frog, called Twisted gastrulation, is an inhibitor of a very important molecule, called bone morphogenic protein (BMP), that determines the fate of early embryonic cells. Twisted gastrulation, or Tsg, is found in both invertebrates, such as insects, and vertebrates, such as frogs and humans.

Because BMP is itself an inhibitor of nerve tissue formation, Twisted gastrulation actually promotes nerve cells by inhibiting the inhibitor. In other words, Tsg tells a primitive cell to become a brain cell, instead of say, a skin cell. But it does this indirectly by preventing BMP from relaying its message to cells. Nerve cells, which include cells of the spine and brain, constitute what’s called the neural system.

The work also shows that Tsg binds to both BMP and another protein called chordin, a well-known BMP inhibitor, to form a three-part complex. In addition, the researchers find that Tsg and chordin, when present together, inhibit BMP more efficiently.

“We have found that BMP signaling can be regulated in much more complex ways than we thought,” says Chang, lead author of the paper.

Hemmati Brivanlou, in 1994, pioneered the “default model” of neural induction, which states that early embryonic cells will mature, by default, into neural tissue in the absence of any signals. But in the presence of BMP, cells will become other types of cells, like skin cells; in order for a cell to become neural, BMP must be inhibited by what scientists call neural inducers. So far, five of these inhibitors, also called antagonists, have been identified, including chordin, noggin and follistatin, the third of which was discovered by Hemmati Brivanlou’s lab in 1994. Twisted gastrulation marks the sixth.

Both BMP and its inhibitors have several potential medical applications: BMPs could be used in plastic surgery for burn victims and wound healing, and the neural inducers might lead to the replacement of damaged neural tissue in patients with stroke or neurodegenerative diseases, such as Alzheimer’s or Parkinson’s. In addition, BMPs and their inhibitors are important regulators of bone, cartilage and joint formation and thus may be used in the treatment of bone fractures or diseases associated with skeletal defects, like osteoporosis.

“There are direct medical applications for any modifier of BMP,” says Hemmati Brivanlou.

The new research may come as a surprise to the scientific community: A report published last year inNature claimed that Twisted gastrulation worked together with BMP to inhibit the growth of neural cells in frogs and fruit flies. Hemmati Brivanlou’s results in frogs have been replicated in fruit flies and zebra fish by researchers at the University of California at Irvine and at the University of Wisconsin. All three groups report their findings in the March 22 issue of Nature.

Originally identified in the fruit fly Drosophila, Twisted gastrulation was named after mutant fruit flies lacking the Tsg gene, which appeared twisted while gastrulating. Gastrulation is a crucial stage of embryogenesis when the three germ layers are established and the primary body axes are constructed. It is at this time that the fate of cells is set. Hemmati Brivanlou’s lab is interested in studying the molecular signals that guide the formation and patterning of cells during this early stage of development.

“I am interested in elucidating the signals that establish fate,” says Hemmati Brivanlou. “How do the cells know to become heart, liver or bone?”

One unexpected, yet intriguing, finding to come out of this research involves experiments that monitor the growth of frog embryos from formless mass to complete tadpole. When other BMP antagonists, like chordin and noggin, are injected into the part of a frog embryo that does not normally become a head, a second body axis will develop, along with a second head. Embryos injected with Tsg, on the other hand, mature into tadpoles with one smaller head. Hemmati Brivanlou says that Twisted gastrulation is not as strong an inhibitor as the others and must have some other function yet to be described.

“The story is not complete,” says Hemmati Brivanlou. “We leave the door open.”

Support for this research was funded by a grant from the National Institutes of Health.

Hemmati Brivanlou and Chang’s co-authors include Douglas A. Holtzman, Samantha Chau, Troy Chickering, Elizabeth A. Woolf, Lisa M. Holmgren, Jana Bodorova, David P. Gearing and William E. Holmes, all from Millenium Pharmaceuticals.