NHGRI Genetic Development Researchers Find Trigger for Cell's Internal Compass

NHGRI Genetic Development Researchers Find Trigger for Cell's Internal Compass

Planar cell polarity is the internal compass that orients the position of cilia, left. The illustration on the right depicts the random position of cilia when planar cell polarity is lost.

A tabby cat's fur grows in one direction, perfect for petting. That trait is the result of an embryonic development mechanism called the planar cell polarity signaling pathway.

Now, developmental geneticists from the National Human Genome Research Institute (NHGRI) studying this pathway have found that it also is a key mechanism for the placement of organs and other structures on either side of the body. Their study of left-right asymmetry in vertebrate development, and the role of planar cell polarity in initiating it, appeared in the June 20, 2010 early online edition of the journal Nature.

Vertebrate development requires specific orientation of the embryo's dorsal-ventral, anterior-posterior and left-right axes. "For the development of multi-cellular organisms, you must have cell number and type increase," explained senior author Yingzi Yang, Ph.D., senior investigator in NHGRI's Genetic Diseases Research Branch. "These cells all need proper polarity to know in which directions to migrate, to divide and to contact with each other. This directional information is essential for cells to be organized into functional organs with the right shapes and positions."

Live imaging recording of embryonic mouse cilia. In a control embryo, left, fast and smooth leftward movement can be seen. In an embryo without the planar cell polarity gene, right, movement contained knots and abrupt turns and were often crossed with each other. Watch the videos

Planar cell polarity is the internal compass of the cell and the organ. In their study of mice embryos, the researchers removed two genes essential for planar cell polarity, called Van Gogh like 1 and 2 (Vangl1 and Vangl2). They observed that cilia, or minute hairs that emerge from cells in a specialized embryonic development organizer called the node, grew in random directions with impaired planar cell polarity functions. "Left-right asymmetry is always determined early in embryonic development," Dr. Yang said. "If an error occurs at this point in development, you would have congenital defects. A good example is the heart; there is a left and right ventricle and they need to be properly positioned."

Embryonic development begins with the first cell division to a point at which complex physical structures are formed with coordination of millions of genetically programmed cells. At some point, the symmetry of early embryonic growth must be broken. "We found the earliest step that breaks bilateral symmetry," Dr. Yang said. "When symmetry is broken, the cells on different sides acquire distinct behaviors that, in turn, facilitate function." The researchers observed that planar cell polarity is the mechanism that allows the embryo to interpret anterior-posterior positional information and establishes left-right asymmetry in the development of functional structures.

Developmental biologists have known that left-right axis is established after dorsal-ventral and anterior-posterior axis. What intrigued the researchers is just how the early embryo knows when to interrupt, or break, the symmetry of early embryos to then determine left-right asymmetry.

Planar cell polarity acts on cells in a single sheet called the epithelium, which creates the surface of structures in the body. In normal development, cells in the plane of the epithelium have similar orientations. Individual cells in a tissue field develop coordinately and function together by responding to planar cell polarity, whether becoming a structure in the ear for hearing, the lining of the lung for breathing, or any of the body's myriad organ structures — even the tabby cat's coat.

According to Dr. Yang, the finding is fundamental to the general developmental biology field and to researchers who study WNT signaling, a key signaling pathway in development and adult physiology in a wide variety of organisms including humans. "The finding offers definitive genetic evidence that WNT- planar cell polarity signaling is important," said Dr. Yang. She also anticipates interest by those who study human genetics and regularly see left-right symmetry related defects.

"There are strong clinical implications for our finding," said Dr. Yang. "If cells and tissues don't get polarity right, severe developmental problems may result. There are those cases in which left-right symmetry poses no problem, but in other cases it can be lethal."

The findings are the result of more than five years of research in Dr. Yang's NHGRI lab. In addition to the individual finding described in the study, the researchers generated genetic tools, including Vang1 and Vang2 mutant animal models, which Dr. Yang believes will be helpful for investigations of additional important embryonic development questions.