The goal of my laboratory is to decipher the molecular basis of neural/epidermal induction and patterning in the vertebrate embryo using Xenopus as a model system. We have shown that the determination of neural fate requires inhibition of BMP/GDF signaling, members of the TGFbeta growth factor family. Inhibition occurs in vivo in the dorsal ectoderm during gastrulation, and is mediated by factors emanating from the organizer. In ventral ectoderm, signaling by BMP/GDF leads to the induction of epidermis. I propose to continue the dissection of the TGFbeta signaling pathway, underlying ectoderm formation at the molecular and embryological level, by taking two approaches: First, to use DNA microarrays to systematically analyze neural inducers, for their transcriptional response in ectodermal cells. This will reveal genes whose expression is either unique or consistently modified by all neural inducers and thus genes implicated in the initial acquisition of neural fate. Second is the characterization of an evolutionarily conserved BMP modulator, Twisted Gastrulation (TSG). We show that TSG antagonizes BMP signaling. I propose to investigate binding partners for TSG and address the in vivo relevance of these interactive partners. We will perform loss-of-function approaches in embryos by using both dominant negatives as well as depletion of maternal TSG mRNA. The TGFbeta pathway has been evolutionarily conserved from C. elegans to humans and has a large range of biological activities. Mutations in these pathways cause various forms of human cancers and developmental disorders. The findings derived from these studies will extend beyond their relevance to embryology, and they will provide significant insights into many fields in biology and medicine.
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