Biomedical Engineering Reference
In-Depth Information
and a founding member of the ErbB receptor family, EGFR has been implicated
in countless physiological and pathological contexts (1,2). Most commonly,
EGFR is activated by extracellular ligands. Ligand binding induces dimerization
of the receptor and activates the kinase in its cytoplasmic domain. By recruiting
and phosphorylating the cytoplasmic targets, the activated receptor couples to
signal transduction pathways and controls cellular responses (see also the pre-
ceding chapter 2.2, by Subramanian and Narang). While experiments in cell
culture keep providing invaluable insights into the structure and function of the
EGFR network, more complex experimental systems are required to study
EGFR signaling in tissues. Co-culture models and cultured tissues can be used
to probe EGFR signaling in multicellular systems (3,4). Finally, analysis of the
organism-level effects of EGFR signaling requires studies in vivo.
EGFR activation in vivo is mediated by autocrine and paracrine signals.
Secreted ligands usually bind to receptors on the ligand-producing cells or their
neighbors. Receptor activation depends on the rates of ligand release, receptors
levels, and tissue architecture. Typically, ligand/receptor levels and activation of
downstream pathways are assessed using in situ hybridization or immunohisto-
chemistry. Since these techniques are nontrivial to quantitate, even the "sim-
plest" parameters of autocrine and paracrine networks, such as ligand
concentrations, cannot be measured directly. In contrast, in the studies con-
ducted in vitro, one can both control the exogenous ligand concentration and
measure receptor levels using a number of quantitative assays.
In theory, modeling and computations can bridge the apparent gap between
the in-vitro and in-vivo studies of EGFR biology (5). Again in theory, the bio-
chemical parameters measured in vitro can provide inputs to the tissue-level
models. These models can estimate the parameters that are either impossible or
difficult to measure directly. For example, the information about receptor dy-
namics generated in cell culture can be combined with the microscopically de-
rived information about the tissue architecture in order to compute the spatial
distribution of autocrine and paracrine signals (6). In this way, cellular and bio-
chemical studies can drive the development of mechanistic models of cell com-
munication in tissues.
The experimental validation of tissue-level models requires a flexible ex-
perimental system. With its advanced experimental genetics, the fruit fly
Droso-
phila melanogaster
serves as an excellent testing ground for validation of
models of EGFR signaling in tissues (7). Further, the high evolutionary conser-
vation makes the
Drosophila
EGFR network an excellent model for the more
complex mammalian EGFR systems (8). In this chapter we first describe two
examples of EGFR-mediated patterning in fruit fly development. These exam-
ples serve to illustrate how EGFR signaling is exquisitely tuned to produce the
appropriate patterns of gene expression during development. Next we describe
some of our initial work in the mechanistic modeling of these systems. Our em-
phasis is on the spatial range of autocrine and paracrine signals and the dynam-
