ABSTRACT

0083653
Glazier

Developing multicellular organisms exhibit dramatic changes in shape and form, as well as the emergence of rapidly changing spatial organization of specialized (differentiated) cell types, e.g. neurons and muscle fibers. These events, which generate the body plan and the various organs, depend on regulated gene expression, elaborate interactions between and among cells, and coordinated cell movement. Gene expression by itself cannot give a full account of the emergence of body plans, specific forms and shapes. Genetics and biochemistry interact with the physical properties of individual cells and cell aggregates in the course of development, making it a multiscale process of enormous complexity. As in many complex processes, however, one can discover dynamical and organizational rules at various levels if appropriate techniques are used to analyze developing organisms. This project brings together biologists, experimental and theoretical physicists, mathematicians, and computer scientists, each of whom has experience analyzing individual biophysical problems, and brings their expertise to bear on a specific developmental process-the formation of the vertebrate limb. Experimental and theoretical methods will be used to investigate the emergence of the limb bud from the body wall, the control of genes mediating cell aggregation, the spatiotemporal regulation of the limb skeletal pattern, and the ingrowth of nerve fibers into the limb from the spinal cord.

This work will result in a multilevel characterization including subcellular, cellular and supracellular mechanisms which will provide a causal understanding of vertebrate limb development, as well as generate analytical tools that can be used to study similar problems in developmental biology. These tools will include software for solving the inevitably complex systems of mathematical equations that describe the interplay of genetic and material properties found in living embryos. New software will be built and distributed to model not only limb development, but also other types of organ formation and illness (e.g. tumor metastasis and vascularization). The overall strategy represents a step towards genuinely integrated research on animal development to deliver on the promise of the gene sequencing projects of the previous decade.

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