| Research in the Scott lab is focused on the mechanisms that determine pattern in the developing vertebrate limb. Why do you have a thumb on one side of your hand, a pinky on the other? Why do you have fingernails on one surface of your hand, fingerprints on the other? Why does your arm have a single bone and your forearm two? Why do you have five fingers? The preoccupation with the mechanisms that regulate pattern formation is based on the structure of congenital limb malformations, many of which appear to be caused by an alteration of one or more of the pattern forming processes. For example, a drug named thalidomide taken by pregnant women as a sedative or anti-nauseate caused severe birth defects in 10,000 children around the world. The most striking of these defects were the limbs that often were missing the long bones of the arm and forearm. The hands could be completely normal except that they were attached directly to the shoulder giving a seal flipper appearance, a congenital malformation known as phocomelia. This is an example of aberrant pattern formation along the proximo/distal axis (shoulder to fingertip), but as yet it is still unclear how thalidomide impacted this developmental process. There are two distinct, but overlapping projects under active investigation. The first involves drugs and environmental chemicals which given to pregnant mice result in offspring which are missing fingers from the posterior (pinky) aspect of their hand. This is an indication that patterning of the anterior/posterior axis has been upset. We are studying Sonic hedgehog biology because the protein encoded by this gene is the major factor that sets up the pattern across the anterior/posterior axis. The second line of investigation utilizes mouse mutants that have congenital limb malformations. We have and continue to identify the genes responsible for these abnormalities. In both projects we examine the intra- and extracellular signaling pathways that are important for normal limb morphogenesis. The work on both projects also uses state of the art technology including gene-targeted knockouts, conditional knockouts in which gene function is deleted in only a single tissue, microarray analysis of the entire mouse genome, various types of in situ hybridizations (to examine mRNA distribution), and immunohistochemistry to follow the proteins that are made from these genes. |
