Cell signaling pathways in development and human diseases
My lab is broadly interested in cell signaling mechanisms that govern cell growth and patterning in animal development. Previous studies suggest that most of the key developmental decisions are regulated by only a small number of evolutionarily conserved families of signaling molecules, including Hedgehog (Hh), Wnt/Wingless (Wg), and other intercellular signaling mechanisms because of its easy access to a combination of genetic, molecular, cell and biochemical analyses. Our general strategy is to identify key regulatory genes essential for Drosophila limb development by genetic screens, and determine the underlying developmental pathways by multidisciplinary approaches.
One major interest is to elucidate Hh signal transduction mechanism in anterioposterior patterning of Drosophila limb. A number of novel components in the Hh signaling pathway have been isolated by our previous genetic screen, and their modes of action are being investigated. For example, our genetic screen has led to an unexpected and important discovery that the cAMP dependent protein kinase, PKA, plays a pivotal role in regulating Hh signal transduction. Our biochemical analysis suggests that PKA may control the processing and activity of Ci, a zinc-finger transcription factor thought to transduce Hh signal into the nuclei. More recently, we have cloned another Hh signaling component called Slimb. Slimb belongs to a newly defined F-box family of regulatory proteins, which includes Cdc4, a yeast cell cycle regulator implicated in the ubiquitin/proteasome mediated proteolytic pathway. Currently, we are testing the model in which Slimb acts in conjunction with PKA to regulate the proteolysis of Ci. Future studies will address how Hh signaling counteracts the negative regulation by PKA and Slimb to stimulate the activity of Ci.
We are also interested in understanding how other related signaling pathways, such as the Wnt/Wg pathway, organize axial patterning and control cell proliferation. In addition, we are interested in identifying downstream effector genes that mediate the biological influence exerted by these signaling molecules. Some of these genes have been identified in our genetic screens and are currently being analyzed.
In human, mutations perturbing Hh, Wnt/Wg and TGFroles in mammalian development and their involvement in human diseases.