Innis, J.W.: Integrative Biology and the Developing Limb Bud

The identification or selective construction of mutations within genes has allowed researchers to explore the downstream effects of gene disruption. Much information has been generated and knowledge has advanced rapidly. However, a limitation in our assessment of the consequences of conditional changes, and thereby our understanding of roles or function, is the degree to which we examine the effects of our manipulations. It is also clear that linear associations are incorrect models for describing development, and newer methods now allow us an opportunity to practice an integrative biology. In our attempts to explore the consequences of Hoxa13 disruption in mice and humans, it has become clear that a full understanding may only be achievable by taking a broader approach with a long-term view. Fundamental questions relative to Hox gene function in vertebrates including how many target genes, what degree of overlap in target genes exists, what magnitude of modulation is exerted, which genes are activated versus repressed, and what classes of molecules are involved need to be explored if a thorough conceptual understanding is desired. To this and other ends, we have undertaken a comprehensive analysis of the expression of genes within developing limb buds of mice. Our efforts will further the 1) exploration of the broader genetic relationships of expressed genes, 2) determination of parallels or variations in target usage for a given gene in different tissues and between different organisms, 3) evaluation of limb patterning mechanisms in other animal model systems, and 4) exploration of gene expression hierarchies regulated by HOX proteins in developmental systems.