Novel epigenetic modes of developmental regulation are being uncovered at a dizzying pace, but the scope of these processes and many of their mechanisms remain poorly understood. This study will investigate how epigenetic changes in protein structure can affect metazoan development. Prions are altered conformations of normal cellular proteins that can affect phenotype by causing a self-perpetuating change in protein function. The ability to adopt a prion conformation is mediated by its prion domain (PrD), a region that tends to contain an unusually high content of uncharged polar amino acids. This unique characteristic of PrDs was exploited to identify in the Caenorhabditis elegans proteome fifteen experimentally tractable proteins that contain putative PrDs (hereafter called CePrDs). To assess whether CePrD display characteristics of known PrDs, the CePrDs will be screened for prion-like behavior in well-characterized yeast assays. The most promising candidate PrDs from the yeast studies will then be studied in detail in their native environment. First, CePrDs will be assayed for their ability to recruit the endogenous, cellular form of their corresponding protein into an altered conformation and to cause changes in the developmental program of the worm. Next, CePrDs will be tested for their ability to transmit a lineage-specific reporter phenotype in worms that is curable by modulation of heat shock protein expression levels. Finally, CePrDps will be examined for their ability to regulate development in the absence of their putative prion domains.