Learning how organs tell left from right

September 16, 1999--From all outward appearances, the human body is symmetrical. If one were to divide the body into two halves, for example, each side would have a single arm and leg. But a look inside at the internal organs shows that there is not perfect symmetry throughout the body. The heart and spleen normally reside on the left side and the liver and gallbladder are on the right. Furthermore, the organs themselves are asymmetrical.

Understanding how genes control the shape and spatial orientation of organs is one of the goals of developmental biologists. In the mouse as in other vertebrates, cells begin receiving and responding to instructions about their positional fate during the earliest stages of development, when the embryo resembles little more than a flat sheet of cells. Two proteins in particular, called Nodal and Pitx2, are produced predominantly on the left side of the mouse embryo and they appear to direct the growth of organs in a way that is appropriately "left-sided." Understanding how these two proteins interact may allow scientists to understand a great deal more about how organs are segregated into left-side and right-side.

In attempting to unravel the genetic program that determines left/right orientation, Howard Hughes Medical Institute (HHMI) investigator Michael Rosenfeld and colleagues at the University of California, San Diego, and The Salk Institute, engineered knockout mice that lacked the Pitx2 gene. The mice exhibited a number of developmental abnormalities, including inappropriate position of the heart and lungs.

Humans with one defective copy of the Pitx2 gene have a constellation of problems called Rieger syndrome, the signs of which include irregularly shaped eyes, lack of tooth growth, craniofacial deformities, and, more rarely, problems with growth hormone production.

Rosenfeld's team found that Pit

Contact: Jim Keeley
Howard Hughes Medical Institute

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