XNF7 AND AXIS DETERMINATION

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The identification of molecules involved in the establishment of the embryonic axis is one of the most important problems in vertebrate development. Recently, a number of growth factors such as activins, FGF, and BMPs as well as secreted factors such as Xwnts and noggin were shown to play important roles in axial patterning. It is likely that many of these serve to establish the prepatterning of the early embryo and operate through signal transduction pathways to activate region-specific genes such as goosecoid, Xlim, Xnot, Xbra at the gastrula stage. Therefore, it is important to identify other molecules that serve as intermediates between the signal transduction pathways and the activation of region- specific gene expression. Xnf7 is a maternally expressed protein that is in the oocyte GV and released into the cytoplasm during maturation. It is retained in the cytoplasm until the mid-blastula transition (MBT) when it enters the nucleus. Overexpression of a dominant negative form of xnf7 (xnf7thr-glu) that inhibits the entry of the endogenous xnf7 into the nucleus at the MBT results in dorsal-ventral axial defects. Our hypothesis is that xnf7 serves as an intermediate between the growth factor-signal transduction pathways and the activation of genes at the gastrula stage. We intent to test this hypothesis by accomplishing the following: (l) To characterize the genetic pathway regulating xnf7 function (2) To further characterize the xnf7thr-glu mutant phenotype and (3) To identify molecules that interact with xnf7 and to identify the xnf7 DNA binding site. The ability of xnf7thr-glu mutant to produce a dominant negative phenotype provides us with a tool to explore the broad issue of dorsal- ventral patterning of the early embryo. It is likely that this analysis will confirm the role of previously described molecules and permit us to discover new molecules involved in this process thereby providing further insights into the molecular basis of axial patterning in vertebrates. This study will also shed light on mechanisms involved in abnormal cell growth and differentiation involved in diseases such as cancer and birth defects.