During vertebrate development, the embryo is subdivided into domains that correlate with eventual specializations in cellular function. The regional expression and function of multiple transcription factors, acting antagonistically and in concert, define unique identities for these domains. Complex interactions among these transcription factors regulate cellular and molecular events that are unique to each tissue. Discovering how positional control of genetic networks leads to cellular form and function is an important step towards understanding the mechanisms underlying human birth defects and disease. The investigators collaborating in this program project have a history of common scientific interests and approaches, all using the zebrafish, a vertebrate model organism particularly suited to genetic, molecular, and embryonic manipulations. The three interrelated component projects will address a common theme: how do particular regulatory genes act to control region-specific cell differentiation? All three projects share a common focus on the roles of transcription factors, especially members of the T-box protein family, asking: what are the required roles of these genes? How is their expression controlled? And, how do combinations of transcription factors act together to regulate downstream effector genes that execute position-specific functions? Each project will study the patterning of a different tissue: the mesoderm germ layer; Kupffer's vesicle, a source of left-right patterning; and the dorsal retina. Comparing results among these systems will allow us to search for general principles by which transcription factors or effector genes act together, as well as to ask whether specific molecular interactions are common to different tissues. In addition to this intellectual synergy, this application will provide common resources to allow cooperation on large-scale experiments that were impossible for each group alone. A Zebrafish Genetics Core Facility will house existing wild-type and mutant fish, generate animals for genetic screens, and provide resources for phenotype analyses. A Molecular Analysis Core Facility will perform sequence-based screening of mutagenized genomes (TILLING), genotyping of identified mutants, and gene expression analysis by semi-automated in situ hybridization. Through interactions between the projects and using the core units, this program will identify new components of the molecular pathways that regulate fundamental steps in vertebrate tissue patterning, discover effector genes that allow cells to express position-specific fates and behaviors, and start to dissect the genetic networks that control positional identity during development. ? ? ?
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