Scientists explain how morphogens work

October 15, 2004

CINCINNATI - Scientists at Cincinnati Children's Hospital Medical Center believe they have answered some critical questions that address how signaling molecules, called morphogens, work.

Morphogens are secreting signaling molecules that play a key role in the formation of the shape and size of organs. For example, these molecules play a role in determining the bean-like shape of human kidneys. But when these molecules malfunction, they can lead to organ defects and cancers. This study provides insights into the mechanisms of organogenesis and could have implications for treating organ defects and cancers.

For years scientists at Cincinnati Children's and elsewhere have sought to determine how morphogens work. In a new study published in the October 15 issue of the journal Cell, Xinhua Lin, PhD, an assistant professor of developmental biology at Cincinnati Children's, concluded that morphogens work by "diffusion."

"These findings provide new insight into the understanding of the mechanisms that control the function of morphogens," Lin said. "In order to treat diseases related with morphogen malfunctions, scientists must first understand the mechanisms that trigger diseases. This understanding can lead to new insight into the possibility of developing new strategies to treat related diseases."

There are several groups of morphogens, but in his new paper, Dr. Lin focuses on TGF beta family molecules that function as morphogens. His interest is in learning how the TGF beta morphogen works.

Developmental biologists have considered and tested several theories that could explain how morphogens work. These theories include extracellular diffusion and transcytosis. In extracellular diffusion, it is suggested that morphogens move across cells by traveling across the surface of cells. Alternatively, the transcytosis model proposes that cells transfer morphogen molecules through endocytosis, which is the incorporation of substances into a cell by pinching off of the plasma membrane.

The Lin study is based on the fruit fly model (Drosophila). He and his colleagues studied the fruit fly protein called Decapentaplegic (Dpp). Dpp is a morphogen molecule that is similar in structure to the human TGF beta protein.

Dpp functions as a morphogen that is instrumental in forming the wings of a fruit fly. The Lin lab demonstrated that Dpp morphogen molecules are mainly distributed on the cell surface, which suggests that Dpp morphogen moves by an extracellular diffusion mechanism.

To prove this hypothesis, Lin and colleagues blocked cell endocytosis and examined Dpp morphogen movement. They found that inhibiting endocytosis disrupts the cell's ability to transduce Dpp signaling, but does not block Dpp movement across cells.

This experiment allowed researchers to distinguish the role of endocytosis in Dpp signaling activity from Dpp movement, providing evidence that endocytosis is not required for Dpp morphogen movement, albeit it is essential for its signaling activity.
-end-
The study was funded by the National Institutes of Health, March of Dimes, Cincinnati Children's Hospital Research Foundation and the American Heart Association.

Cincinnati Children's Hospital Medical Center

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