Salk Scientists Find Genes That Control Limb Formation In Vertebrates
La Jolla, CA – Whether they're wings, fins or legs, those appendages generally known as limbs play a critical role for lifting, grasping, moving and other activities needed to sustain life.
Until recently, little was known about the process that leads to limb formation in vertebrates, from mice to men.
But now scientists at The Salk Institute have identified a family of genes that plays a critical role in triggering the growth of limbs.
According to their study, published in the current issue of the journal Cell, these genes – from the Wnt family – interact with another set of previously identified growth factors to induce limb formation in chick embryos.
The findings not only shed light on how limbs originally develop, they also might offer new clues into how other structures form in the body, including the heart, lung and other organs.
"What we're seeing may not only be happening in limbs, but the action of these two families of growth factors could be very important for the genesis of a wide range of organs in the body," said Juan Carlos Izpisúa Belmonte, a professor in the Gene Expression Laboratory at Salk and the principal author of the Cell paper.
The latest study builds on earlier research from Izpisúa Belmonte's laboratory showing that extra limbs could be induced to grow in embryonic chicks by implanting beads soaked in fibroblast growth factor (FGF). Those results, reported in 1995, represented a breakthrough in the understanding of limb determination.
Since then, researchers in Izpisúa Belmonte's lab have been trying to find other factors that might influence or control this activity. Members of the Wnt gene family (for "wingless," originally discovered in fruit flies) were viewed as logical targets since they have been shown to interact in a variety of developmental systems, including tracheal development in fruit flies; neural patterning in frogs; and brain, tooth and kidney development in other vertebrates.
In their current series of experiments, Izpisúa Belmonte's team inserted three different members of the Wnt family into viruses which, in turn, were implanted into the flanks of chick embryos.
The results suggested that each of the Wnt genes (Wnt-2b, Wnt-8c, Wnt-3a) were responsible for turning on two forms of FGF, each of which controls both limb initiation and a bud or bulge known as the apical ectodermal ridge (AER), which acts as the "organizer" of limb development.
Izpisúa Belmonte noted that the interaction of FGF and Wnt signals could be involved in a variety of developmental processes. For example, one study recently showed these signals act in concert to induce development of the inner ear.
"It will be interesting to investigate whether Wnt pathways also interact in this way with FGFs in other regions of the embryo where FGFs are also known to play an organizing role, such as the brain, lungs and other structures," said Yasuhiko Kawakami, a member of Izpisúa Belmonte's team.
Also participating in the study were Salk scientists Javier Capdevila; Dirk Buscher; Tohru Itoh, and Concepcion Rodriguez Esteban. Support for the study was provided by the National Science Foundation, a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists, the National Institutes of Health and the G. Harold and Leila Y. Mathers Charitable Foundation.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. The Institute was founded in 1960 by Jonas Salk, M.D., with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.