For cells to be good neighbors, they need gap junctions, communication channels formed of proteins on the outer membrane that allow adjacent cells to coordinate their activities and movements. New research from several teams is now showing that abnormalities in the proteins that form gap junctions, which are called connexins, can lead to a wide range of defects in mice, including heart malformations, infertility, and cataracts. Similar defects occur in humans, and researchers hope that understanding these abnormalities in animals will lead to ways to prevent the problems in people. "The mouse experiments tell you where to go to look for problems [in humans]," says neurobiologist David Paul of Harvard Medical School in Boston.

One gap-junction defect already shown to cause a human developmental problem affects the protein called connexin43. Last year, William Fletcher, a molecular biologist at the Loma Linda University School of Medicine in California, and his colleagues established that the connexin43 gene is mutated in some children who need heart transplants because their hearts failed to develop the asymmetry needed to supply enough blood to the lungs. Another research group showed that knocking out this gene in mice also causes malformations in that part of the heart, which kill the animals at birth.

More recent work, described at the meeting by developmental biologist Cecilia Lo of the University of Pennsylvania, Philadelphia, has helped pinpoint just where connexin43 comes into play during heart development. She used DNA from cytomegalovirus to cause an extra copy of the connexin43 gene to become active in the neural crest, which gives rise to the peripheral nervous system, but also has cells that migrate to what becomes the heart's right ventricle and the pulmonary artery. They seem to help the heart become asymmetrical, Fletcher notes.

At birth, Lo's mice have defects, such as an obstructed pulmonary artery, that are "strikingly similar to those that have occurred in people," says Fletcher. Preliminary data from Lo's group suggest that the heart defects in the mutant mice arise because the neural crest cells move too fast to the heart. Thus, they may not be in the right place at the right time to get, or give, the signals needed for normal heart growth.

Gap-junction disruption can also lead to abnormalities of other organs. At the meeting, Paul's Harvard colleague Alexander Simon described experiments in which his team made mice that lack the gene for the gap-junction protein called connexin37, which forms junctions between the oocytes and surrounding tissue. The resulting females were infertile: It seems their oocytes never received the right signals to mature into eggs and leave the ovary.

Also in these mice, there was a premature change in the tissue surrounding the oocyte, which normally transforms into the progesterone-secreting corpus luteum after ovulation occurs. Because this change occurred in the connexin37 knockouts in the absence of ovulation, Simon concludes that immature oocytes need connexin37 to inhibit this transformation. The ovaries in these infertile mice resemble those of women with spontaneous premature ovarian failure syndrome, a problem leading to premature menopause, he notes. "It would be nice to look at the DNA of [these women]," Simon says, to see if they too have abnormal connexin37.

The effects of lacking another connexin, connexin46, show up in the eye, as Xiaohua Gong, a graduate student in Norton Gilula's lab at the Scripps Research Institute in La Jolla, California, reported. Eliminating the gene for this protein does not inhibit the formation of the lens, but does cause cataracts to begin to develop in mice about a month after they are born. "The connexin is important for maintaining lens transparency," says Gong. Learning more about what happens in the animals may help explain cataracts in people, he adds.

And Paul thinks the connexin connection to human disease is just beginning. "I bet we'll see a variety of disease-associated [connexins]," he predicts.