Monya Baker

Ascl2, a transcription factor and Wnt target, switches on a stem cell program in the gut

In the search for what makes a stem cell a stem cell, Hans Clevers and colleagues at Hubrecht Institute-KNAW, the Netherlands, have found a transcription factor expressed uniquely in the gut1. Deletion of the gene, called Achaete scute-like 2 (Ascl2), completely ablates stem cell activity. Activating the gene in non-stem cells causes the cells to take on stem cell characteristics, including making stem cell markers and reproducing the structures and specialized cell types that normal intestinal stem cells produce.

Previously, Clevers had done complex cell- and lineage-tracking experiments both to establish Lgr5 (leucine-rich repeat-containing G protein—coupled receptor 5) as a marker of stem cells in the small intestine and to pinpoint the location of intestinal stem cells at the base of crypts, or the spaces between villi.

In the current work, the researchers used Lgr5 to isolate intestinal stem cells and then compared gene-expression patterns between the stem cells and other cells in the intestine. There were surprisingly few genes that were expressed exclusively in the stem cells.

The researchers decided to focus on Ascl2, a transcription factor whose expression is controlled by the Wnt pathway. The bewildering Wnt pathway relies on several interacting proteins to transmit signals from outside and inside the cytoplasm into the nucleus, and it is also implicated in differentiation processes from very early embryogenesis to tissue maintenance and repair in adults.

A series of experiments established Ascl2's role: expressing the transcription factor in non-stem cells caused crypts to form, whereas deleting the gene in the small intestine caused the stem cell population to disappear. A search of Ascl2 binding sites indicates that the protein binds the promoter region of Lgr5.

Ascl2 is present in colon cancer tumours, and Clevers speculates that the gene could be responsible for converting cells to cancer stem cells. More broadly, however, the identity of a single gene that turns on a tissue-specific stem cell program demonstrates how the intestine provides a valuable model system for studying stem cells in vivo.

"There will be other transcription factors like Ascl2, waiting to be discovered," says Clevers. "Some will be under the control of Wnt, others won't."



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