Key gene’s role in embryonic development identified

Expectant parents often delight in the ultrasound images of their developing baby and the way its body slowly comes to resemble a fully formed child.

Today’s developmental biologists are finding a less sentimental but equally compelling kind of fascination as they use the tools of advanced molecular science to understand how various genes interact to guide embryo development. Their findings take us forward – towards better understanding of what can go awry – and backward — to appreciating the conservation of genes throughout millions of years of evolution.

A study by researchers at the UW Medical School and the University of California-Irvine is one of three in the March 22 issue of Nature pinpointing what one particular gene does to shape the dorsal (back) area of developing embryos. The research teams found that the Tsg (twisted gastrulation) gene acts together with another gene to suppress the action of a family of growth factors, bone morphogenetic proteins (BMPs). The suppression of BMP activity in turn changes the identity of cells that would have developed into tissues associated with the belly of the embryo into cells that will become tissues associated with the embryo’s back.

“We have helped identify the players in a very critical developmental stage,” says Daniel Greenspan, professor of pathology and laboratory medicine. “Close relatives of these molecules in the fruit fly and frog also occur in mammals, so this finding helps the research community better understand embryo development in a wide range of species, including humans.”

To understand the significance of the finding, consider what scientists know about normal embryonic development. Shortly after fertilization, stem cells in the organism take the form of a hollow ball of cells called a blastocyst. The blastocyst starts aligning along the three axes (straight lines around which cells grow) that shape the final organism: top to bottom, left to right, and front to back (ventral to dorsal). This last line helps to determine which organs will develop on the belly of the animal and which will develop towards the back.

The process of cells relocating to their proper positions in the blastocyst is called gastrulation, and it depends on a very complex interplay of chemical signals throughout the embryo. Scientists have known for more than 75 years that this axis is influenced by what certain cells communicate to other cells nearby. What hasn’t been clear is which signals are being sent, by which genes, and for what purpose. If that information were clearly understood, scientists could identify what goes wrong in abnormal development.

In the fruit fly, just seven genes are responsible for development of the dorsal-ventral axis (or back-to-belly development). One of those genes is called “SOG” for “short gastrulation.” In vertebrates – including mice and the African clawed toad studied by the UW researchers – the gene chordin does the same thing that “SOG” does.

SOG and chordin also are known to block the activity of BMPs. In so doing, they block some kinds of cells from proliferating and allow other kinds to flourish. UW and California researchers reported in the Nature paper that Tsg works along with SOG and chordin to block the signals the BMPs are sending.

Focusing on genes and gene products helps identify the molecular defects producing human disease. The Greenspan team’s work, for example, may have long-term implications for certain kinds of birth defects. Mutations in other genes that affect BMP signaling have already been associated with infertility and cardiovascular defects in mammals.

The findings also buttress developmental biology’s contribution to the understanding of human evolution.

“We see similar genes turning up in different organisms and performing many of the same functions,” says Greenspan. “It is becoming more clear that some kinds of patterning are controlled by a molecular framework that has been conserved from very, very ancient forms of life.”

The other groups with Tsg papers in Nature are from Howard Hughes Medical Institute in Minneapolis and The Rockefeller University in New York.