MATH1 signal heralds process of differentiation in intestinal lining

December 06, 2001

HOUSTON - When Dr. Huda Y. Zoghbi, professor of pediatrics, neuroscience, and molecular and human genetics at Baylor College of Medicine and members of her lab first began studies of the role the gene Math1 plays in the intestine, they anticipated that it would affect the nerves there.

Instead, they discovered that Math1 and the protein associated with it plays a critical role in determining the fate of stem cells or early progenitor cells in the epithelium or lining of the intestine. Early in development, every organism consists of a small set of identical cells. Those cells become the different tissues of the body depending on the chemical signals to which they respond. The process is called differentiation. In this case, the intestinal cells in which Math1 is active become one of three types of secreting cells -- Paneth, goblet or enteroendocrine -- found in the intestinal epithelium.

"It was a puzzle," said Dr. Qi Yang, a postdoctoral student in Zoghbi's laboratory who was first author on the study that appears in the Friday (Dec. 7) issue of the journal Science. Co-authors include Dr. Zoghbi, Dr. Milton Finegold, professor of pathology at Baylor and Nessan A. Bermingham, PhD, another postdoctoral student.

In previous studies, Math1 had been linked to the nervous system. For instance, it was shown to be critical to development of tiny "hairs" in the ear that make it possible for people to hear.

"It was a surprise for us to find it expressed in intestinal cells," said Zoghbi, who also is a Howard Hughes Medical Institute investigator. "It tells us is that this gene is important in a variety of cell types. "For a long time, scientists have known that there were different cell types in the gut and that they were derived from stem cells," she said. "Now we have a factor that would differentiate those stem cells into ones that secrete and one that absorbs."

In the future, understanding how the intestine develops could play an important role in developing new therapies for chronic diseases such as inflammatory bowel disease, said Dr. Susan Henning, a professor in the gastroenterology section of the department of pediatrics at Baylor.

Because tumors of the small intestine are so rare, "you could flip this around and say understanding this pathway may lead us to understand why the small intestine has so few tumors," said Henning. The finding could also lead to therapeutic approaches to diseases such as necrotizing entercolitis, a major killer of premature infants in which parts of the intestine literally die.

However, such therapies are likely far in the future, she said. "I see therapeutic implications whenever we move ahead on fundamental understandings," she said. "This is an important step forward in our basic understanding of how this complex epithelium develops."

"This kind of pioneering work is an example of unexpected new discoveries coming to one area of science from outstanding investigators who originally were doing basic research in another field," said Dr. Mary Estes, a professor molecular virology, microbiology and medicine at Baylor and director of the new Texas Gulf Coast Digestive Diseases Center that is funded by the National Institutes of Health.

Baylor College of Medicine

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