Amy Kiger
|
 |
Functional Genomics of Cellular Morphogenesis
Changes in cell shape, or morphogenesis, are central to cell function, development and disease. The regulation of cell morphology can be viewed as a complex system that must integrate the temporal-spatial control of multiple cellular processes, including cytoskeletal and membrane dynamics, cell adhesion and growth. Are there stereotypical morphogenetic networks that coordinate this complexity to form distinct cell shapes? To understand morphogenetic programs, we are applying an informative combination of functional genomics and in vivo genetic approaches in Drosophila to the problem of cellular elongation.
Specifically, we are using genome-wide RNAi screens, live cell imaging, Drosophila developmental genetics and bioinformatics to study how a hormonal cue culminates in cellular elongation. These studies have also led us to investigate how phosphoinositides provide spatial information in the cell to mediate morphological responses that impact cellular elongation in development and disease.
Cellular elongation is a morphological feature
common to many cell shape changes, observed from yeast budding
to polarized
blood cell migration. Elongation involves many gene functions
for coordination of axis selection, cytoskeletal re-orientation
and directed membrane growth. Throughout Drosophila development,
the hormone ecdysone triggers cell elongation within morphogenetic
programs. Addition of ecdysone to Drosophila blood cell lines
also induces a stepwise change in cellular elongation, providing
a simple, relevant model for morphogenesis that can be genetically
mapped to comparable events in fly development. We are using
this cell-based system for comprehensive functional genomic analyses
of cellular elongation, with a goal to build morphogenetic network
models that we will test in the context of Drosophila development.
Our cell-based functional studies have identified kinases and phosphatases that phospho-regulate specific phosphatidylinositol phosphate lipids (PIPs) important for cellular elongation. Certain PIPs are known to spatially distinguish membrane compartments and regulate a broad range of cellular processes. Thus, the regulatory mechanisms that in turn control these phospho-regulators are key to understanding how PIPs and associated pathways spatially define cell shape. Importantly, a number of PIP phospho-regulators are associated with human diseases that result from cell morphology defects. For example, mutations in phosphoinositide 3-phosphate phosphatases have been implicated in both muscle myopathies and neuropathies, attributed to defects in the maintenance of elongated muscle and neuronal cell types. We are using cell and developmental genetics to investigate PIP pathways and mechanisms that provide spatial information in the cell to mediate morphological responses, ultimately using knowledge gained from Drosophila functional genomics for new inroads into molecular mechanisms of these diseases.
Functional genomics is an ideal approach to comprehensively probe the genetic networks that regulate cell shape. We pioneered a widely applicable functional genomic technology using RNA-interference (RNAi) in Drosophila cells that now permits unprecedented genome-wide loss-of-function analysis of metazoan cell morphology. Our RNAi microscopy screens have identified gene functions required to maintain distinct round or flat blood cell morphologies, including many previously uncharacterized genes. This work established a cellular 'mutant collection' of specific and classifiable phenotypes, serving as a foundation for ongoing research into functional genomics of cell shape changes, such as hormone-induced cellular elongation.
"The key to every biological problem must finally be sought in the cell, for every living organism is, or at some time has been, a cell." (E.B. Wilson, 1925, The Cell in Development and Heredity)
Selected Publications
Eggert, U. S., A. A. Kiger, C. Richter, Z. E. Perlman, N. Perrimon, T. J. Mitchison and C. M. Field. (2004). Parallel chemical genetic and genome-wide RNAi screens identify cytokinesis inhibitors and targets. PLOS, 2(12): e379.
Schlesinger, A., A. Kiger, N. Perrimon and B.-Z. Shilo. (2004). Small wing PLC-gamma is required for ER retention of cleaved Spitz during eye development in Drosophila. Dev. Cell, 7(4): 535-545.
Boutros*, M., A. A. Kiger*,
S. Armknecht, K. Kerr, M. Hild, B. Koch, S. Haas, R. Paro, N. Perrimon.
(2004). Genome-wide RNAi analysis of
growth and viability in Drosophila cells. Science, 303:
832-835.
*equal authorship
Kiger, A. A., B. Baum, S. Jones,
M. Jones, A. Coulson, C. Echeverri, N. Perrimon. (2003). A functional
genomic analysis of cell morphology
using RNA-interference. J. Biol., 2: 27.
Kiger*, A. A., D. L. Jones*, C. Schulz, M. Rogers
and M.T. Fuller. (2001). Stem Cell Self-Renewal Specified by JAK-STAT Activation
in
Response to a Support Cell Cue. Science 294: 2542-2545.
*equal
authorship.
Kiger, A. A., H. White-Cooper and M.T. Fuller. (2000). Somatic support cells restrict germline stem cell self-renewal and promote differentiation. Nature 407: 750-754.
Amy Kiger received her Ph.D. as a Howard Hughes Medical Institute Predoctoral Fellow from the Department of Developmental Biology at Stanford School of Medicine. She then completed postdoctoral studies in the Department of Genetics at Harvard Medical School as a Fellow of the Jane Coffin Childs Memorial Fund for Medical Research.
