Wnt Signal Regulates the Geometry of Dividing Stem Cells

For organisms to develop and grow, asymmetry is essential. New research from Howard Hughes Medical Institute scientists reveals how a localized source of a signaling molecule directs a dividing stem cell to produce two different cellsone identical to its parent, the other a more specialized cell typeand aligns those cells. In a developing tissue, such oriented divisions will position cells to migrate to the right place to ensure the right architecture.

This kind of asymmetry is a universal aspect of how organisms grow, says Roel Nusse, an HHMI investigator at Stanford University, explaining that dividing cells must orient themselves appropriately to create the asymmetrical bodies of complex organisms. In a paper published March 21, 2013, in the journal Science, Nusse and his collaborators show that a protein called Wnt3a coordinates the orientation of the two different cell types that are generated when a dividing stem cell undergoes an asymmetrical division.

Theres all kinds of geometry going on, regulated by the signals between cells. But when you add growth factors to a tissue culture medium, theres no orientation effect. Roel Nusse

Stem cell division with Wnt-3a bead: When grown with a Wnt3a-coated bead (blue), embryonic stem cells divide such that one daughter cell is proximal to the Wnt3a signal, and the other daughter cell is distal to the signal. Segregating chromosomes of the dividing cell are seen in orange.

From: Habib, S.J., Chen, B., Tsai, F., Anastassiadis, K., Meyer, T., Betzig, E., and Nusse, R. 2013. Science.

Wnt3a is one of a large family of Wnt proteins that play important roles in controlling how organisms develop and grow. Nusse and Harold Varmus discovered the first Wnt gene in mice in Varmuss lab at the University of California, San Francisco in 1982. Since then, Nusse and others have shown that Wnt proteins play key roles in embryonic development, tissue regeneration, bone growth, stem cell differentiation, as well as many human cancers.

To study how Wnt proteins affect cells, researchers typically add the molecule to the nutrient-rich solution in which laboratory-cultured cells are grown. Nusse and his team recently showed that when Wnt3a is given to embryonic stem cells in this way, it helps the cells maintain their identity as stem cells, rather than differentiating into more specialized cells. But experiments like these dont really reflect the ways cells in a living organism receive signals, Nusse says.

Most of the signals that cells in tissues make for each other are received by neighboring cells, he says. So theres an orientation effect: the signal comes from one end of the cell and it only activates the target cell at one side. Theres all kinds of geometry going on, regulated by the signals between cells. But when you add growth factors to a tissue culture medium, theres no orientation effect.

Shukry Habib, a postdoctoral researcher in Nusses lab, came up with a way to recreate that orientation effect with cells grown in a dish. Rather than adding Wnt3a to the tissue culture medium, he attached it to tiny beads. When he added the Wnt-coated beads to dishes in which embryonic stem cells were growing, the scientists could then watch individual cells that were close enough to a bead to receive a Wnt3a signal, and track the fate of the new cells as they divided.

Nusse says the first experiments with the Wnt3a beads were underway when he attended a meeting of HHMI scientists and met with Eric Betzig, a lab head at the Janelia Farm Research Campus. In 2011, Betzigs team developed a high-speed, high-resolution, three-dimensional imaging technology that they call the Bessel beam plane illumination microscope. The microscope gives extraordinarily detailed views of cellular processes in action, and as Betzig and Nusse talked, they realized it could be a powerful tool in tracking the stem cells response to the Wnt-coated beads.

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Wnt Signal Regulates the Geometry of Dividing Stem Cells