Well-known Protein Helps Stem Cells Become Secretory Cells

Described in the May 15 issue of Development, the finding improves understanding of how cells become specialized for secretion, which is a critical ability of certain glands and cell types in organisms from insects to humans.

The researchers discovered that a protein called CrebA single-handedly controls the entire set of events leading to secretion in the fruit fly’s salivary gland and epidermis, its skin-like outer layer.

CrebA, or a closely related human gene, might play the same role in certain human cells, too, the researchers say.

In juvenile (type I) diabetes, for example, pancreatic cells that normally produce and secrete insulin don't work, and stem cells might be able to help fix that problem, the researchers note. “The key is knowing how pancreatic cells know what hormones to produce and release, or how any gland does, and the new findings add to that knowledge,” says Deborah Andrew, Ph.D., professor of cell biology in Johns Hopkins' Institute for Basic Biomedical Sciences.

Curiosity brought Andrew and Elliott Abrams, then a graduate student, to focus on secretion in the salivary gland, the largest glandular organ in the fruit fly embryo, approximately six years ago. In humans and in fruit flies, the gland secretes saliva, a fluid containing water, mucus, electrolytes, and food-dissolving enzymes, into the mouth, and is important to the digestive system.

In their new experiments, the researchers looked at the expression of 34 secretory genes in a normal fruit fly embryo to see which genes were turned on when. All 34 genes were expressed at high levels in the early salivary gland, they found. According to Andrew, “This suggests the salivary gland becomes programmed for secretion because all the components required to allow secretion to occur are ‘turned on’ very early in development.”

In order for any gene's instructions to be used to make a protein, the process of reading the instructions is jump-started by proteins called transcription factors. In the salivary gland, the researchers found two of these proteins that controlled secretory gene expression in the salivary gland: CrebA (Cyclic-AMP response element binding protein A) and Fkh (Fork head).

CrebA is required for the expression of the secretory genes throughout development, while Fkh appears to be required only in later embryonic stages. The group has shown that Fkh is required to maintain expression of CrebA in the salivary gland. “CrebA is the more immediate factor involved in keeping secretory genes expressed at high levels, and Fork head acts through it,” said Andrew.

CrebA’s role in the fruit fly’s epidermis gives it secretion-promoting powers there as well, the researchers note. In fruit flies, epidermal cells secrete the cuticle, a protective covering for the organism.

“Our findings suggest that this single transcription factor directly determines the amount of secretory activity in a given cell type,” said Andrew.

Funding for the study was provided by the National Institutes of Health.
Development 132, 2743-2758 (2005)