It took almost 10 years for Elaine Fuchs, Ph.D., a Howard Hughes Medical Institute investigator at Rockefeller University, to find a postdoctoral fellow who shared her curiosity for the direction of cell divisions in the skin. Then Terry Lechler, Ph.D., came along and the result is a new paper published online last week in Nature detailing how asymmetric cell divisions are essential for skin development.
Their findings challenge long standing ideas of how skin forms and functions and is one of the first documentations of asymmetric cell division in mammals.
The epidermis of the skin forms multiple layers, the outermost of which is at the body surface. The bottom, or basal, layer is attached to an underlying matrix, called a basement membrane, which contains many growth stimulating molecules. As cells move from the basal layer toward the surface, they differentiate and produce protective proteins before they finally die and are sloughed off.
"The epidermis creates a Saran Wrap seal for our body surface, keeping fluids in and harmful bacteria out," says Fuchs, who is the Rebecca C. Lancefield Professor and head of the Laboratory of Mammalian Cell Biology at Rockefeller. "Through experiments in cell culture in the 1980s, everyone believed that the epidermis maintained its protective function by ejecting cells from the basal layer and forcing them upward. Our data show that asymmetric divisions occur perpendicular to the basal layer, resulting in one of the two daughter cells being naturally displaced out of the basal layer. This opens up new ways to approach the pathology of different skin diseases and provides an explanation for how stem cells might generate one new stem cell and one differentiating cell at the same time."
Lechler first documented how often he saw cells in the basal layer of skin in mice dividing perpendicularly to the basement membrane below the bottom layer of cells. He found that at least 75 percent of all the cell divisions he observed were in this orientation.
"It was obvious from the first few mice that I looked at that not only did perpendicular divisions occur, but they were extremely common," says Lechler. "We can't rule out that some cells detach from the bottom layer and migrate upwards, but this is most likely a minor component of skin stratification."
He then turned to flies for help. Asymmetric divisions, and the proteins involved in selecting the division direction, are well documented in fruit flies. Specifically, the proteins Inscuteable and Pins form a complex that anchors one pole of the machinery that drives division to the top, or apical, side of the cell, leaving the other pole at the base of the cell. This defines the axis of the division plane. Lechler found the mammalian equivalents of these proteins and looked to see whether or not they were involved.
"Anywhere Terry saw a cell whose division plane was oriented perpendicular to the basal layer, he saw the Inscuteable complex forming on the apical side of the cell," Fuchs says. "It was the first time that this complex, involved in asymmetric divisions in fruit flies, has been implicated in a similar fashion in mice. And it is fascinating that asymmetric divisions turn out to control skin differentiation."
But not everything works exactly the same. Lechler also discovered that integrin and cadherin proteins contribute to the asymmetric divisions in the epidermis. Integrins are proteins that anchor cells in the bottom epidermal layer to the basement membrane, and cadherins are important in maintaining adhesion between cells so they can create the barrier that keeps harmful bacteria out. Neither have been previously shown to be involved in asymmetric divisions in the fly. However in mice, if these proteins are mutated or missing, the cells don't divide properly.
"Our data help us to understand how cells are able to detach from the basement layer and move upward," Fuchs says. "When the cells divide asymmetrically, so that one daughter cell sits atop of the other, the cell on top is already detached from its basement membrane rich in growth factors. Without integrins and growth factors, the top cell is already different from the bottom cell. Thus, an asymmetric division creates a natural way of partitioning growth-promoting and differentiation-promoting factors."
Other tissues and cell types may also use asymmetric cell division to create daughter cells that are different. Most notably stem cells may use this mechanism to create progeny where one cell stays the stem cell, but the other cell goes on to differentiate.
"Now that this system is set up, it will make it very easy to go on and study asymmetric cell division in other tissues and in the stem cell compartment," says Lechler. "It will also be interesting to look at different skin disorders and cancer to see if the divisions are perturbed, and whether that is contributing to pathology of the diseases."