ANTEROPOSTERIOR ECTODERMAL PATTERNING IN XENOPUS

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DESCRIPTION (provided by applicant): The long-term goals of this project are to understand the molecular mechanisms responsible for determination and patterning of the presumptive neurectoderm (dorsal ectoderm) of the frog Xenopus laevis. The goals of this proposal are to ask how the neurectoderm is first set aside, by exploring how expression of a marker gene is restricted to the presumptive neurectoderm. In a subtractive cloning screen to define very early markers of neural pattern, the Sive lab isolated opl, which encodes a zinc finger protein, a member of the zic gene family. Opl is expressed throughout the presumptive neurectoderm during gastrulation. In ectodermal explants, opl expression can be activated by the Bone Morphogenetic Protein (BMP) antagonist Noggin and by Wnt3a. We will connect the activities of the secreted factors Noggin and Wnt3a with activation of opl expression. Although BMP antagonists have been strongly implicated in neural determination in Xenopus, the mechanism by which removal of BMPs activates downstream genes is not understood. Similarly, Wnt proteins are implicated in posterior neural patterning and general neural determination, but the mechanism by which they activate neurectodermal target genes may be complex. Regions of the opl promoter responsive to Noggin and to Wnt3a have been defined in explants. These sequences will be further analyzed and compared to those required to restrict opl expression to the neural plate of transgenic embryos. A factor(s), which interacts with the Noggin-responsive element will be identified. Phylogenetically conserved elements in the opI promoter will be defined. Many birth defects affect the neural tube, however their genetic cause is generally not understood. This proposal will define normal developmental mechanisms and therefore give insight into causes of abnormal development. The mechanisms through which signal transduction pathways change expression of neurectodermal target genes is poorly understood, and abnormal responses to signaling molecules play a role in multiple diseases, including cancers. This proposal will help define mechanisms by which abnormal response to a signaling event is elicited.