Morphogen Dynamics Integral to Stem Cell Differentiation

Significant differences between the methods signaling pathways use to prompt cells to differentiate have been uncovered. Specifically, Rice University scientists led a team that discovered stem cells are sensitive not only to the signals that form the "instructions" to create the pattern of the organism, but to how rapidly those signals are delivered.

The lab of Aryeh Warmflash set out to see if the amount of the signaling molecule was the primary cue for instructing the cells what to become.  The answer was clearly "no" for one of the highly related pathways they studied—and, surprisingly, "yes" for the other.

Their paper, published in eLife this week, details the activities of two signaling pathways, Nodal and BMP4, in experimental models of early mammalian embryos.  Both pathways are integral to gastrulation. BMP4 triggers the process and defines the "ventral" or belly side of the embryo, where skin will form. On the opposite side, where BMP is low, the nervous system develops. When cells are exposed to BMP, it sustains change for as long as its triggering ligand is present.

In contrast, the Nodal pathway, which causes cells to become muscle, the heart and other organs, is controlled by how its target cells sense and adapt to changes in the environment, especially to changing levels of its ligand.

The researchers concluded interactions between these ligands, called morphogens, and cells are far more dynamic than previously thought, and not merely dependent on ligand concentration.

Recently, the lab determined the WNT signaling pathway that carries signals across a cell membrane depends upon context for its actions. Nodal and BMP4 are part of the TGFb superfamily of proteins. The researchers found they alter how cells respond to WNT.

"What's true for WNT is even more so for the TGFb pathways we looked at this time," said Warmflash, an assistant professor of biosciences. "For WNT, we highlighted how the same pathway can be deployed in different ways depending on context. This paper highlights how different pathways that function in parallel, almost in the same context, get used differently."