In this week's journal Nature, scientists at the Salk Institute for Biological Studies report that they have solved one of the "holy grail" puzzles of developmental biology: the existence of a mechanism that insures that the exterior of our bodies is symmetrical while inner organs are arranged asymmetrically.
In research with zebra fish, as a model for human biology, Juan-Carlos Belmonte and his Salk Institute colleagues found that retinoic acid (vitamin A) is the signal that buffers the influence of asymmetric cues in early-stage embryonic stem cells and allows these cells to develop symmetrically.
In the absence of retinoic acid, the exterior of our bodies would develop asymmetrically, with the result being that our right side would be shorter than the left one.
"On the outside, the human body looks very symmetrical," says Yasuhiko Kawakami, a senior research associate in Belmonte's Gene Expression Laboratory and the first author of the Nature paper. "But, inside the human body, the pattern of the organs is asymmetrical. For example, we don't have two stomachs, one located on the right and the other on the left. We have one stomach, located on the left half."
A complex cascade of signals helps generate the three-dimensional body pattern of the zebra fish as well as the human body. Patterning of the body occurs along three main axes: the head to toe, which arranges organs and structures (front, eyes, nose, mouth, jaw, neck, shoulders, etc.) sequentially; back-front, which distinguishes our back from our front; and left-right, which distinguishes our left and right parts.
The novel findings reported by Belmonte's team illustrate how the development of the antero-posterior and left-right axes is coordinated by vitamin A. Retinoic acid exerts its influence at the stage when the embryonic stem cells enter the node region of the embryo and begin forming the embryo's three main layers of cells that organize into the brain and nervous system, the gastrointestinal tract, and other systems of the body.
Cells in the vicinity of the node are instructed to behave differently depending on whether they are on the left or right sides of the embryo. The action of retinoic acid makes sure that some of those cells ignore the left-right instructions and progress symmetrically.
Belmonte compares the node to a doorway. "Before embryonic stem cells enter the node, they don't have an orientation. Nor are they differentiated into specialized tissues -- such as heart or brain cells," he said. Once through the doorway, embryonic stem cells have their marching orders: they "know" where to locate themselves in the developing organism and what to differentiate into.