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.

"Paradoxical," is the Salk scientists' description of retinoic acid signaling in the uniform ball of cells that is the early embryo, because its signaling influences both the asymmetric arrangement of organs and tissues in the interior of our bodies and the symmetrical pattern of the exterior of the trunk.

Belmonte and his Salk colleagues evaluated other signaling pathways that also influence pattern formation -- Wnt, fibroblast growth factor and Notch -- and found that none of them was responsible for coordinating the antero-posterior and left-right axes. However, blocking the retinoic acid pathway generated an uneven distribution of tissue on the right and left halves of the body. That is, somites (which give rise to the vertebrae and other body structures that are symmetrical) were unevenly distributed on the right and left axis. Normally, equal numbers of somites occur on each side.

In addition to improving scientific knowledge about early development, these research findings are relevant to the future development of treatments based on embryonic stem cells.

As explained by Salk senior research associate Angel Raya and co-first author of the Nature paper, the stem cells for such therapies will have to be coaxed into becoming specific cells, such as heart cells. As he noted, "they also will have to be 'instructed' about their orientation in the body. These cells need to know more than what to become. They need to know how to pattern a fully-functional structure or organ."

"Only by studying the behavior of stem cells within the embryo will we be able to understand how these cells are instructed to give rise to specific cell types that interact to form structures with proper morphology and function," Belmonte added.

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