Our lab is interested in the genetic control of patterning:  how a simple egg is programmed to generate the great tissue complexity of adult organisms.  We address this question using the genetically tractable fruit fly Drosophila melanogaster, which has a long and successful history for generating insights into the development of complex organisms.  Recently we have begun to address the role of metamorphosis in determining the final adult form of the fly, an area that has been surprisingly sparsely researched, despite the inherent fascination we all have for this process.  (Almost every child has at one time or another watched a caterpillar form a chrysalis around itself, and waited with unchildlike patience for a beautiful butterfly to emerge.)  Although not widely appreciated, we have found that a great deal of patterning occurs during the pupal period, and that the steroid hormone response gene E93 regulates much of this patterning.  The mode of action of E93 appears to be as a pupal-specific cofactor for many of the genes necessary to remodel the worm-like larva into the adult insect form.  Recent work from other labs has demonstrated that there is a global alteration in the genes targeted by some regulatory proteins at the larva to pupa transition.  We have demonstrated that E93 is directly responsible for one of these shifts in target gene response:  E93 promotes the development of bract cells in the fly legs by integrating spatial cues from the Epidermal Growth Factor (EGF) signaling pathway with a temporal signal derived from the steroid hormone Ecdysone.  Since mutations in the E93 gene affect most of the structures patterned in the pupa, it is likely that E93 will be found to have a role in many of the target gene response changes in the pupa, an area that we are actively investigating.   This work is likely to have direct clinical relevance:  there are known human E93 homologues, and human growth and maturation is regulated by steroid hormones.  In addition, mutations in EGF signaling have been implicated in several human cancers.

We have for many years investigated the roles of several other genes in the development of the adult: we cloned and characterized spineless (ss), a gene necessary to pattern the adult olfactory organs (the antenna and maxillary palps).  We showed that ss is homologous to the human dioxin receptor (Ahr), which mediates the toxic effects of dioxin in mammals.  We are continuing to investigate the role of ss in olfaction and looking for the relationship between the seemingly disparate functions of Ss and Ahr.  In addition, we have made considerable progress in elucidating the genetic circuitry that patterns the adult abdomen, a process which occurs almost completely during the pupal period.  Both of these research areas are now tied together with our analysis of E93, since the pattern of the antenna, maxillary palps and the abdomen are all disrupted in E93 mutations, and preliminary evidence suggests that Ss may directly interact with E93.  Our future goals will be to determine the extent to which E93 patterns the pupa, whether other E93-like genes also contribute, and to gain insight into the molecular mechanisms by which E93, ss and other pupal patterning genes work.

Finally, in conjunction with Yehuda Ben Shahar and Barani Raman, we are excited to be involved in the NSF-funded Neuronex consortium. Neuronex is dedicated to development of tools and techniques to further the analysis of brain function in a large variety of vertebrate and invertebrate organisms. Our labs’ contribution will be to develop and utilize CRISPR/Cas methodologies to probe neural function in the Orthopteran Shistocerca americana — the American Bird Locust. It has been quite the learning curve to step outside of the Diptera to the much older (and bigger) order of the grasshoppers !