As a laboratory of developmental biology, our guiding interest is to comprehend how complex biological patterns can be assembled with stereotyped precision. This requires a detailed understanding of how cells come to execute appropriate behaviors — be it adoption of specific cell fates, proliferation, or apoptosis — and do so at the right times, in the right places, and in the right numbers. Dysfunction of processes that direct normal tissue patterning results not only in developmental disorder but also underlies adult disease. Tellingly, many factors whose mutation is relevant to human cancer were first identified and characterized with respect to development in model organisms. To study these topics, we utilize integrative approaches, combining genetics, biochemistry, and genomewide approaches, to elucidate detailed molecular mechanisms and use these to understand in vivo biology as well as decipher genomic regulatory networks.
We have extensively utilized the fruitfly Drosophila melanogaster, based on its wealth of sophisticated genetic tools and depth of comparative genomic data. We focused on two topics in developmental patterning: (1) determination of cell fates by a cell-cell signaling cascade known as the Notch pathway and (2) the biological activities of microRNAs, a class of endogenous small regulatory RNAs. We study these with respect to the development of several fly tissues that are intricately yet robustly patterned. For example, the body surface of the fly is covered with mechanosensory bristles, which constitute most of its peripheral nervous system (Figure 1). The pattern of bristles is very stable in wildtype flies but is readily amenable to genetic manipulation.
By studying how PNS patterning and other settings are altered by manipulating Notch signaling, lineage transcription factors and microRNAs, we have uncovered new strategies regarding developmental patterning. Moreover, our mechanistic and genomic studies have yielded broadly conserved concepts regarding transcriptional gene regulation, small RNA discovery and biogenesis, and mRNA processing (e.g. tissue-specific alternative 3’UTR utilization [Fig. 2], circularization, and RNA methylation). We have subsequently extended many of these principles into mammalian systems, including into aspects of mouse development.