Summarizing the results of these studies, which are published in the September 16, 1999, issue of the journal Nature, Rosenfeld said, "the work shows that the control of the left/right orientation of organs is more complicated than we thought."

Researchers knew that Nodal is a signal-carrying protein, and Pitx2 is a transcription factor -- a protein that turns on other genes. Once the Nodal signal arrives, it induces Pitx2 to help implement its directives. One testable issue in the current study, says Rosenfeld, "was to determine whether Pitx2 implements the entire Nodal program or whether Nodal acts via additional targets."

The results of earlier experiments that attempted to untangle the functions of Nodal and Pitx2 were intriguing, but did not produce a clear answer. When researchers added Nodal or Pitx2 to the right side of a mouse embryo, for example, the right side developed as a mirror image of the left. In other experiments, researchers added extra Nodal or Pitx2 to embryos only to find that the two proteins had similar effects. And knocking out the Nodal gene alone resulted in either mirror-image or randomized organization of multiple organs.

Given these results, Rosenfeld says he would have expected the knockout of Pitx2 to cause the same sort of organ abnormalities reported by scientists who performed the Nodal knockout experiments.

The actual result was a mixed bag, but it appears that Pitx2 is crucial in determining the "leftness of the lung," say Rosenfeld and his colleagues. Without Pitx2, both sides of the lungs of the knockout mice looked like the right side of a normal lung. The left side of a normal pair of lungs is usually smaller to accommodate the position of
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
16-Sep-1999