Myxococcus xanthus represents an excellent model system to address fundamental questions of how cell-cell signaling pathways control multicellular development. These questions are relevant to all normal embryonic and adult cells which transduce signals to coordinate processes such as growth and differentiation, as well as to cells which are defective in signaling networks, such as cancer cells. Progression through early multicellular development requires that M. xanthus cells sense and respond to a high cell density and nutrient limitation. Two sensitive sensing networks which monitor these extracellular signals converge at a critical check point early in M. xanthus development. This check point can be monitored by expression of a specific gene, 4521; only if the conditions are correct for early M. xanthus development is this gene expressed. The long term goals of this research are to determine: i) How do the cells sense and transduce the cell-density signal? ii) How are the cell-density-and nutrient-sensing pathways integrated? iii) What is the connection between the change in gene expression and the complex behavioral response of multicellular fruiting body formation? To answer these questions our research focuses on identifying and characterizing the circuitry that connects the cell-density signal, extracellular A signal, to its responsive gene. The techniques of classical and molecular genetics, combined with protein biochemistry, will be used to characterize the A signal transduction pathway. We expect through this investigation to also gain insights into the mechanism by which M. xanthus integrates cell density and nutritional information. Specifically, we propose: i) to characterize the structure and function of sasB locus, a negative regulator of 4521 expression, thought to be a component of the A signaling pathway; ii) to identify and characterize the cis-acting elements controlling 4521 expression by mutational analysis; iii) to identify and characterize direct regulators of 4521 expression by purifying and characterizing proteins that bind to the 4521 upstream regulatory region. The genes encoding these proteins will be identified and characterized by DNA sequence analysis and mutagenesis; iv) to identify by genetic analysis additional components of the A signal pathway; and v) to characterize other early A signal-dependent developmental promoters by cloning, localizing, and sequencing these regions.
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