Spared Ribs

					                                                                                                                  N E W S & N O T E S
                                                                                                                                                                           mal function. And because almost all human

                                                                                                                 Spared Ribs                                               genes have counterparts in mice, knockout
                                                                                                                                                                           mice serve as valuable laboratory models for
                                                                                                                 Genetic patterning of skeletal struc- learning how genes work in humans.
                                                                                                                                                                                Capecchi pioneered the techniques for
                                                                                                                 tures offers insights into evolution. knocking out mouse genes two decades ago
                                                                                                                         cientists have known for some time                and continues to refine them. In this case, he

                                                                                                                 S       that certain genes affect the way our
                                                                                                                         shapes ultimately shape up—how we
                                                                                                                 develop physically. Now, researchers have
                                                                                                                                                                           and Wellik focused on Hox genes, long
                                                                                                                                                                           known to be essential for controlling embry-
                                                                                                                                                                           onic development in practically all animals.
                                                                                                                 pinpointed two families of genes suspected of Hox genes encode molecular switches, Capec-
                                                                                                                 playing a central role in the “master plan” of            chi explains. They turn many other genes on
                                                                                                                 how vertebrate skeletons are sculpted.                    and off, thereby orchestrating cascades of
                                                                                                                      In a demanding series of experiments,                developmental changes in the body. One
                                                                                                                 Mario R. Capecchi, an hhmi investigator at                obstacle in understanding precisely what Hox
                                                                                                                 the University of Utah School of Medicine,                genes do, however, is that there are so
                                                                                                                 and postdoctoral fellow Deneen M. Wellik                  many—39 in mammals—and each one con-
                                                                                                                 (now an assistant professor at the University of trols perhaps hundreds of target genes. These                 Mario Capecchi studies the skeleton’s “master plan.”
                                                                                                                 Michigan) discovered the roles of two groups              multiple Hox genes, termed paralogs, arose
                                                                                                                 of genes in orchestrating the construction of             during evolution through gene duplication            gous genes. Making the Hox11 knockouts pre-
                                                                                                                 the ribs, spine, and limb bones. Their work               and share similar DNA sequences.                     sented an even tougher challenge because the
                                                                                                                 appeared in the July 18, 2003, issue of Science.               On top of this complexity, laments Wellik,      Hox11 triple heterozygotes were essentially
                                                                                                                      The geneticists used “knockout mice,”                is the issue of “functional redundancy,” the         sterile: The males died shortly after sexual
                                                                                                                 breeds in which the genes under investigation             bane of all geneticists. Typically, two or more      maturity, and the females couldn’t implant
                                                                                                                 have been removed or inactivated by genetic               Hox genes act together as a work group. If           embryos. So Wellik had to generate offspring
                                                                                                                 engineering. By examining what goes wrong in only one of the genes is knocked out, the oth-                    embryos using in vitro fertilization and then
                                                                                                                 a mouse lacking the contributions of a partic- ers can carry the load, and the mouse will                      implant the embryos into surrogate mothers.
                                                                                                                 ular gene, biologists can infer that gene’s nor-          hardly be affected. So to really understand               But the Herculean efforts paid off. When
                                                                                                                                                                                     what the genes are doing, one has to       Wellik examined her prized mice, she saw
                                                                                                                                                                                     disable all the genes in a work group.     some remarkable anomalies in the animals’
                                                                                                                   Vertebrae Display In a normal mouse skeleton
                                                                                                                   (top photo), the ribs end at T13, the 13th thoracic, or
                                                                                                                                                                                     That’s what Wellik did—in this case,       skeletons. Those missing all of their Hox10
                                                                                                                   chest, vertebra. The lumbar (lower back) and sacral
                                                                                                                                                                                     to the paralogous Hox10 and Hox11          genes had misshapen limbs, confirming suspi-
                                                                                                                   (pelvic) vertebrae form normally. But when Hox10 genes
                                                                                                                                                                                     gene sets, which each contain three        cions from prior research that Hox10 controls
                                                                                                                   are disabled (bottom photo), ribs grow from vertebrae all
                                                                                                                                                                                     member genes.                              skeletal patterning. But even more striking
                                                                                                                                                                                          Her undertaking might be              were their rib cages: Instead of having a nor-
                                                                                                                   the way from the chest to the tail.
                                                                                                                                                                                     described as heroic, although Wellik       mal one around the chest, the mice had ribs all
D E N E E N W E L L I K , U N I V E R S I TY O F U TA H ( M O U S E ) ; PAU L F E T T E R S ( C A P EC C H I )




                                                                                                                                                                                     confesses in retrospect that “I’ve         the way down to their tails. The Hox11 knock-
                                                                                                                                                                                     heard other adjectives, such as nuts,      out mice, in addition to having malformed
                                                                                                                                                                                     insane….” Capecchi wouldn’t go that        limbs, lacked all sacral vertebrae—the bones
                                                                                                                                                                                     far, although he does say that “I’m        that normally attach to the pelvis. Remarkably,
                                                                                                                                                                                     amazed she was willing to do it.”          pointing back to the functional redundancy of
                                                                                                                                                                                          Mice, like most animals, carry two    these genes, mice containing just a single nor-
                                                                                                                                                                                     copies of each gene, one from each         mal copy of any of the genes didn’t exhibit
                                                                                                                                                                                     parent. To produce mice with both          these drastic skeletal transformations.
                                                                                                                                                                                     copies of each of the three Hox10               It appears as if the primordial body plan
                                                                                                                                                                                     genes inactivated, Wellik first had to     was to have ribs along the full length of the
                                                                                                                                                                                     generate mice with just one of each        spine, says Capecchi. He believes that the
                                                                                                                                                                                     pair disabled (termed “triple heterozy-    Hox10 genes evolved, after water dwellers first
                                                                                                                                                                                     gotes”) and then interbreed them.          ventured onto land, to become master regula-
                                                                                                                                                                                     From those crosses, only rare pups         tors of spine development and shut off devel-
                                                                                                                                                                                     were born with the sought-after trait      opment of the extraneous ribs.
                                                                                                                                                                                     of missing all six copies of the paralo-                                  —PAUL MUHLRAD



                                                                                                                                                                                                                                      hhmi bulletin | december 2003                    37

				
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