Pattern formation along the dorsal-ventral (DV) embryonic axis is fundamental in the establishment of the diverse cell types found in vertebrate embryos. A Bone Morphogenetic Protein (BMP) signaling pathway is key in this pattern formation process. BMPs are postulated to act as morphogens to establish distinct cell fates along the DV axis. Current models for dorsal-ventral patterning and the BMP signaling gradient are still rather basic in nature, however, due to difficulties in addressing key questions regarding BMP gradient action. A number of new molecular genetic tools, combined with unique cellular methods in the zebrafish, will be exploited in this proposal to significantly extend upon the current models of vertebrate DV patterning. Two issues central to models of DV patterning and BMP signaling will be investigated. First the temporal action of the BMP gradient in DV patterning will be tested using inducible transgenes. It will be determined if the gradient acts coordinately during gastrulation to specify all ventrolateral cell fates or if it acts at multiple time points. Secondly, spatial aspects of the BMP signaling gradient will be examined. An effective gastrula BMP signaling gradient range will be defined under normal physiological conditions, which actively specifies distinct cell types during a given time period in vivo, key properties of morphogens. The spatial extent of the gradient will be examined functionally. Lastly, to maximize understanding of DV patterning and BMP gradient generation, regulation, and action through loss-of-function studies, it is critical to identify all the genetic players in the pathway. To this end, an uncharacterized dorsalized mutant gene will be analyzed, which may be a novel component of this pathway. These studies are directly relevant to the study of human disease, since some of the genes in this pathway have been shown or are implicated in the cause of multiple human disease states and human inherited disorders. ? ?
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