Q&A with Jeremy Nance, Ph.D.
Assistant Professor, Department of Cell Biology
Program for Developmental Genetics, Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine

Developmental geneticists investigate how embryos develop into organisms. The long-term goal is to decipher the genetic programs that regulate development and to understand how those might go awry in disease. Jeremy Nance, Ph.D., works with the nematode C. elegans as a model of human development. In a paper recently published in Science, Dr. Nance and his colleagues describe how a genetic signal helps early embryonic cells move to an appropriate position in the embryo. They focused on a protein called PAR-6, which uses its location to tell cells which side is in and which is out. The question is: What tells PAR-6 which side it's on?

Q. You work with C. elegans, the worm made famous in the 1990s as the first multi-cellular organism to have its complete genome sequenced. What can we learn about human development by studying a worm?
A. C. elegans is cheap, it develops very quickly, yet it has many of the same genes that humans do. It's possible to very quickly manipulate the genome, make mutations, perturb gene function, and see what consequences those manipulations have on the development of the organism. The worm doesn't look very much like a human, but if you look carefully at the cellular level and at the signals cells send each other as the embryo develops, those same signals are functioning in worms that function in human development. We can learn quite a bit at the very basic level about how cells talk to each other, how they move around to reorganize the embryo, how they know what to become.

Q. Isn't that the focus of your work, and your recent paper in Science?
A. Yes. In all animal embryos at a very early stage the cells undergo migrations, called gastrulation, to reorganize themselves. For example, the cells that will make up the intestine must end up on the interior of the embryo. Often these cells are born on the surface of the embryo so they have to migrate inside. Gastrulation occurs very early, well before organs begin to form. In humans it begins 3 weeks after fertilization. If there are problems in gastrulation, they can have catastrophic consequences. All of these movements rely on cells knowing their position in the embryo and their position relative to one another.

Q. How do cells know that?
A. Cells learn to distinguish the surface that faces their neighbors from the surface that faces the outside of the embryo by sensing contacts with one another through radial polarization, which happens even before gastrulation. A protein called PAR-6 is involved in polarizing all different types of cells. For example, how do the cells in your intestine know to have microvilli on one surface that would help them absorb nutrients? The cells have to be polarized to build the structures on that particular side of the cell.

Q: What happens in the worm embryo?
A: In the worm embryo, PAR-6 is initially localized all around the surface of the cell. Then, as the embryo begins to polarize radially, cells sense contact with one another and PAR-6 disappears from the contacted surfaces and is restricted to the outer surface of the embryo. We wanted to know how a cell distinguishes those different surfaces. We understood from previous work that PAR-6 is a key player in radial polarization. We knew that if we removed it, the cells did not polarize normally and gastrulation was defective. What we didn't understand was how that worked: What was the link between a cell touching another cell and the exclusion of PAR-6 from the adjacent surfaces?

Q. How did you find the answer?
A. We searched for mutations in genes that would prevent PAR-6 ever from becoming localized, so that instead of being restricted to the outer surface, it would be found around the entire surface of each of the cells and therefore they would fail to polarize. We found the responsible mutation within a gene we named pac-1, rather inelegantly for "PAR-6-at-contacts." It immediately told us a lot about how this polarity was working and what the connection was with the cell contacts. The first thing we showed is that pac-1 has the opposite localization of PAR-6—it is recruited to the sites of cell contact. We could show that it was the cell contacts themselves that recruited pac-1 to the sites. That was a very exciting finding.

Q: You are working with very early-stage worm embryos. Does your work shed any light on the biology of stem cells, which have received so much attention because of their extraordinary ability to transform themselves into cells of almost any tissue? 
A: Although worm embryos do have cells that behave like stem cells, I’m most excited about the prospect that our research will shed light on the formation of embryonic stem cells in humans.  Cells in the early human embryo, like those in C. elegans, respond to contact with one another and asymmetrically position PAR-6.
The pattern of contacts appears to be critical in separating embryonic stem cells from cells that make extra-embryonic tissues such as the placenta.  Stem cells arise from the internal cells that are contacted on all sides and that have lost PAR-6 at their surface.  It’s not known how cell contacts regulate the formation of embryonic stem cells, and it’s tempting to speculate that similar genes control polarity of cells in the worm and in humans.  So one hope is that those studying embryonic stem cells will be able to use what we learn in C. elegans to determine how cell contacts induce embryonic stem cell formation.