How cells acquire, transfer and interpret positional information to shape the developing embryo is a fundamental embryological question. Positional information is involved in important developmental processes including embryonic induction, differential competence of the responding tissue, and cytoplasmic specification. The long term goals of this research are to understand the role of hormonal signaling in establishing positional information in the early embryo and physiologic function in the adult. One class of information transfer is mediated by morphogens, diffusible chemicals responsible for causing morphogenesis. An interest in identifying novel morphogens led the investigators to design a strategy where candidate nuclear hormone receptor homologs were first isolated from a developmental system and then used to identify the corresponding ligand. Xenopus was chosen as a model because it affords an ideal combination of embryological and biochemical approaches to study embryonic signaling while remaining an appropriate model for higher vertebrates. The hypothesis is that identifying new signaling systems will provide important insights into positional specification during embryonic development. The investigators previously isolated and characterized a novel nuclear receptor activated by a class of endogenous substituted alkyl benzoates. These compounds comprise a novel class of hormone receptor ligand and are related the B-complex vitamins p-aminobenzoic acid and folic acid suggesting a further link between development and nutrition. This BXR (benzoate 'X' receptor) represents a hitherto unknown hormonal signaling pathway.
They aim to fully characterize the BXR signaling pathway during Xenopus development and subsequently extend these results to mouse and human. They will exploit the unique accessibility of the early Xenopus embryo to experimental manipulations to I) test the effects of locally increasing or decreasing BXR signaling during development, 2) Identify the true endogenous ligand for BXR in Xenopus embryos and bovine serum, 3) determine the temporal and spatial localization of the BXR ligand during early development, and 4) Isolate and characterize mammalian homologs of BXR. Aberrant signaling processes, especially those related to cellular identity, are particularly relevant to cancer and its treatment. Identification of developmental signaling molecules and their receptors could lead to the identification of novel morphogens, teratogens, and hormones. Moreover, because nearly all hormones regulate cell growth and differentiation they and their antagonists are natural candidates in the treatment of human disease, especially cancers.
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