Ph.D. Dartmouth College
During animal development, cells proliferate, migrate and rearrange to form tissues and build complex organs. To simplify these tasks, cells separate into regionally distinct cell groups to carry out their specialized functions. Long-range intercellular signaling separate fields of cells, and short-range, local cell-cell signals refine these subdivisions to form sharp, stable boundaries between cell groups. Cell fate boundaries are critical to tissue patterning: in some cases they serve to draw the detailed features of mature tissue; in other instances, they anchor specialized cell signaling centers - organizer tissue - that direct the fates of surrounding cells. Cell fate boundary formation is recognized as a basic developmental strategy with sundry examples. These include in Drosophila the wing margin and leg segments, and in vertebrates the somites, the rhombomeres, forebrain and the limb bud. The molecular mechanisms underlying cell fate boundary formation are poorly understood.
We use Drosophila oogenesis as a model system to understand the genetic and molecular basis of cell fate boundary formation. We have identified a role for the bunched gene in cell fate boundary formation. bunched is differentially spliced to encode a set of proteins similar in structure to members of the TSC-22/GILZ family of trancription factors. TSC-22/GILZ family members are conserved in all animals and are associated with human cancers and mammalian immune function. We have shown that Bunched is required to pattern specialized features of the fly eggshell during oogenesis. In the fly, Bunched is regulated by EGF and TGF-b morphogen signals; in turn Bunched regulates short range Notch signaling to establish an epithelial cell fate boundary.
The broad, long-term aims of our research are to discover the conserved molecular cell signaling pathways that establish cell fate boundaries, a fundamental problem in developmental biology. Our short term goals are to: (1) characterize the role of three Bunched isoforms in bun-dependent cell fate boundary patterning in vivo; and (2) characterize the role of Bunched isoforms in regulating target gene expression both in vivo and in a cell culture functional assay; and (3) identify Bunched target genes important in cell fate boundary establishment. These tests of bunched structure and function will place the gene in a conserved pathway essential to cell fate boundaries formation and with relevance to aberrant tissue patterning - including tumor formation and metastases.