We use genetic and biochemical approaches to study three areas of developmental biology. These are:
Planar cell polarity (PCP) in epithelial cells:
The establishment of cellular polarity is a crucial step in the development of epithelial tissues. Polarization along the apical/basal axis is a universal feature of epithelial cells and is important for specialized epithelial functions such as vectorial transport. In addition to apical/basal polarity, the epithelial cells of many tissues are also polarized along an axis that is orthogonal to the apical/basal axis. This form of epithelial polarity is known as planar cell polarity or tissue polarity. Examples include the sensory cells of the ear and the hairs on the wing cells of the fly. Many studies have suggested that the orientation of planar polarization is directed by a gradient of signaling by the Frizzled transmembrane receptor protein across the tissue. Since Frizzled class proteins are known to be able to act as receptors for Wnt class ligands, this has led to the suggestion that long-range gradients of Wnts provide the positional information directing the direction of PCP. However, no such Wnts have been found despite a great deal of effort. In our recent work on the fly eye, we have uncovered a novel mechanism for directing PCP in a Wnt-independent manner. This mechanism involves the graded expression across the tissue of a cadherin-class transmembrane protein (Dachsous) that regulates Frizzled signaling through the action of another cadherin superfamily member (called Fat). Interestingly, Fat has been previously implicated as an important regulator of epithelial cell growth. We are currently investigating the detailed biochemical mechanisms underlying this novel signaling system and its role in cellular polarity and growth.
The control of cell shape, motility and the actin cytoskeleton by Src family protein tyrosine kinases:
Dynamic regulation of the actin cytoskeleton is a key feature in coordinated cell movement and cell shape changes. Much evidence suggests that protein tyrosine kinases of the SRC family (SFKs) play a key role in regulating actin cytoseletal rearrangements. We study the role of the SFKs in this process by analyzing the role of the SRC64 protein in regulating the actin cytoskeleton and cell movements during Drosophila oogenesis. We have shown that SRC64 regulates the growth dynamics of actin-based structures called ring canals as well as the movement of follicle cells during oogenesis. We are now seeking to identify the precise biochemical pathways by which SRC64 has these effects. Among our discoveries is another tyrosine kinase, TEC29, that is a target for SRC64 regulation. We anticipate that these studies will shed light on the role of SFKs in many actin-based processes in other tissues including cell migration, metastasis in the case of tumor cells, and the formation of axonal growth cones.
control of cell fate specification by receptor tyrosine kinases: