Modeling Biological Networks

• IV.6.vi Subproject 6 – Transcription Factor Responses and Regulatory Networks in Drosophila Development
  • IV.6.vi.a Introduction
  • IV.6.vi.b Advantages of the Drosophila Model
  • IV.6.vi.c Datasources
  • IV.6.vi.d Microarray Methodology
  • IV.6.vi.e Specific Aims
  • IV.6.vi.f Research Plan
    • IV.6.vi.f.1 Aim 1
    • IV.6.vi.f.2 Aim 2
    • IV.6.vi.f.3 Aim 3
  • IV.6.vi.g Significance
• [ Other Subprojects ]

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IV.6.vi Subproject 6 - Transcription Factor Responses and Regulatory Networks in Drosophila Development:

The Drosophila Genomics Resource Center (DGRC) with The Center for Genomics and Bioinformatics (CGB) is producing a Drosophila whole genome transcriptional array. This array will allow direct determination of expression levels and their time sequence for all Drosophila m. genes, which will provide the input data for extensions of Subprojects 1-4. Based on the experience in yeast, we expect that the existence of a gene expression database will lead to new, unanticipated correlations and to the assignment of genes of known and unknown functions to newly discovered cellular pathways. In collaboration with the DGRC, we intend to create a modified array representing transcription factors. This array will be simple and inexpensive to use and we expect it to catalyze widespread efforts to develop the kind of tissue- and stage-specific catalogs of changes in regulatory gene expression that the analyses of Subprojects 1-4 require.

We will test the array by documenting changes in the expression of transcription factors in two tissues, the metamorphosing salivary gland and hormone-treated Kc cells, and use these data to develop network models for genes and their expression patterns.

To analyze gene regulation networks as they coordinate development - i.e. for a "functional genomics of development" -- we require two kinds of data: (a) genetic results revealing the biological connections among genes (i.e. suppressor-enhancer studies of gene-interactions), and (b) reliable databases recording the expression of all genes (and, eventually, all protein forms) on a cell-by-cell and moment-by-moment basis. We do not have complete records of either kind for any multicellular organism, but Drosophila has much to offer as the target of such efforts.

Drosophila is the most-thoroughly-studied metazoan genetic/molecular system: its genome has been sequenced, large collections of mutations exist, and additional screens to mutate all its genes are underway. The wealth of existing genetic and developmental information concerning Drosophila, coupled with powerful techniques for its genetic manipulation, make it an outstanding model for fundamental studies of gene regulation in development. The last decade has revealed that Drosophila is also an exceptionally good model for studying regulatory and developmental problems because of the remarkable conservation, of both sequences and molecular pathways, between Drosophila and mammals. More than 60% of human disease genes are present in flies, including genes involved in cancer, neurological disease, malformation syndromes, metabolic disorders, and diseases of the cardiovascular, renal, hematological, immune, and other systems.