Migratory pluripotent neural crest cells (NCCs) are a novel vertebrate invention that generates an astounding variety of tissue types. From the peripheral nervous system to endocrine and craniofacial structures, NCCs contribute the distinguishing features of many organs. Prior to their migration to various target destinations throughout the embryo, NCCs must undergo induction along the neural plate, specification, and then delamination from the neuroepithelium. Although some of the major regulators of NCC induction and specification have been identified, the control of delamination and the initiation of migration remain poorly understood. Characterizing how sets of stationary pluripotent cells are transformed into directionally migrating streams of tissue precursors may have major implications for understanding vertebrate development and evolution, but may also reveal how non-migratory cells lose their cell adhesions and become metastatic in pathological conditions.
The aim of this project is to take advantage of recent technological developments to conduct functional genomics as well as high-throughput reverse genetics approaches to identify new regulators of NCCs prior to the initiation of migration. The recent availability of the zebrafish genome sequence as well as comprehensive microarray platforms and fluorescently activated cell sorting techniques (FACS) make the zebrafish an excellent model for conducting these experiments. Specifically, identifying the targets of known transcriptional regulators of NCC, such as Snail and LEF1, and conducting time-course transcriptional analysis of NCC development will substantially expand our knowledge of NCC control. In addition, a genome duplication event that affected a zebrafish ancestor provides an opportunity to study ortholdgs which may have undergone sub-functionalization, thereby releasing some genes from earlier functions beyond which other vertebrates (e.g. chick, mouse, or frog) fail to develop when their single copy is mutated. Understanding how cells move during normal embryonic development can contribute tremendously to our ability to diagnose and treat pathological conditions, such as metastasis, fibrosis, and carcinoma. Many of the genes implicated in these diseases are also thought to be active in early developmental events such as the delamination and migration of neural crest cells. A more thorough analysis of the genes regulating neural crest activity will facilitate the identification of other potential disease regulators that may be useful diagnostic as well as therapeutic targets. ? ? ?
