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."