We do research in two areas:

1) Growth control and epithelial morphogenesis

The control of organ size and shape remains one of the biggest mysteries in developmental biology. Several processes contribute to organ size including cell growth (the accumulation of cell mass), as well as cell proliferation and cell death (the net accumulation of cell number). Organ shape is dependent upon localized changes in cell shape that impose global constrains on epithelial architecture. All these seemingly distinct processes are tightly coupled as abnormalities in one process can influence the other. For example, stimulation of cell growth can lead to cell death, and abnormalities in epithelial cell shape can lead to epithelial overproliferation. A major challenge is to understand how these processes are coupled in normal development, and how their
uncoupling can lead to disease including cancer. At the molecular level, networks of tumor suppressor genes and oncogenes link these processes. Some tumor suppressor genes directly counteract the activity of oncogenes, and, conversely, some oncogenes directly counteract the activity of tumor suppressor genes.

Our objective is to utilize powerful experimental tools available in Drosophila to piece together the regulatory networks that link these processes. Toward this goal we have identified a novel tumor suppressor-oncogene pair. Normally the tumor suppressor counteracts the activity of the oncogene to maintain the correct epithelial architecture and to restrict cell proliferation. Activation of the oncogene bypasses this guard and alters both epithelial architecture and cell proliferation (Figure 1 B-C). Similarly, the removal of the tumor suppressor (Figure1 D) eliminates this guard and leads to a similar phenotype. Our objectives are 1) to determine the biochemical functions of this pair of proteins; 2) to determine their affect on cellular growth, proliferation, death and modulation of cell shape; 3) to identify additional components acting in this pathway that may directly link the control of
epithelial cell shape to cell proliferation.

Figure 1: Genes affecting epithelial shape and proliferation. A) Expression of the Green Fluorescent Protein (GFP) in mosaic clones (labeled in green), in disc epithelia, does not alter epithelial shape or
proliferation. We are interested in genes whose activation or removal such as these shown in panels B-D simultaneously affects epithelial shape and proliferation. (B-C) Ectopic expression of a novel oncogene either uniformly (B), or in mosaic clones marked using GPF co-expression (C) cause abnormalities in epithelial shape and cell proliferation. (D) Removal of a novel tumor-suppressor gene, in mosaic clones (marked by the loss of the green label), causes similar abnormalities (see text for detail).

2) Developmental signaling
An important feature of embryogenesis is the establishment of signaling centers across developing tissues and organs. Secreted peptide signals emanating from these signaling centers control cellular proliferation, differentiation and tissue morphogenesis. Although much has been learned about the establishment of these signaling centers, little is known about how the signals themselves spread between cells, interact with receptors on the cell membrane and elicit diverse physiological responses. We are using the Drosophila embryonic epidermis as a model system to address such questions. In this tissue the potent peptide signals Hedgehog and Wingless emanate from localized sources to control epidermal cell differentiation. Through the analysis of mutants that disrupt cellular responses to Hedgehog and Wingless signaling we have identified a number of genes that are used repeatedly during development to control patterning and morphogenesis (For a general review see Trends in Genetics 17:574).
Three of these genes, drm, lines and bowl display related developmental phenotypes (For the initial characterization of lines and drm see Genes & Development 14:1364; Development 129:3645). We have determined that these three genes encode components of a novel pathway. Competitive protein-protein interactions between Drm and Lines and between Lines and Bowl regulate the nuclear accumulation of Bowl, the key effector of this pathway, across epithelial layers (Figure 2). In turn, the pattern of Bowl accumulation across the epithelium prefigures the pattern of epithelial cell differentiation. As a putative C2H2 zinc-finger transcription factor Bowl may control expression of key cell fate regulators in response to Hedgehog and Wingless signaling. Our current objectives are 1) to complete the functional characterization of these proteins; 2) to determine how this novel pathway operates in patterning and morphogenesis; 3) To explore conservation of regulatory mechanisms in vertebrates.

Figure 2: drm and lines influence Bowl protein accumulation in opposite ways. A) In the wild type, the endogenous Bowl protein accumulates across the embryonic epidermis in two cell rows per segment. However, in drm mutants the accumulation of Bowl is much reduced (B), whereas in lines mutants the accumulation of Bowl is broad (C).