Molecular mechanisms of N-myc gene regulation during mammalian embryonic development

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The development of a multicellular organism from the fertilized egg is a complex process involving differential expression of the genetic information in a precise spatial and temporal pattern. In mammals, embryonic development involves early differentiation events, which permit the embryo to survive in the uterine environment, as well as a process during which a pool of pluripotential cells proliferates and subsequently diverges to generate the fetal primordia. Highly complex morphogenetic events, together with organogenesis, will then establish the definitive body plan of the fetus. The interdependence of various parts of the developing embryo suggests some form of hierarchical control in which signaling molecules and transcriptional regulators interact to modulate the activity of groups of structural genes in a concerted fashion. The identification and the characterization of genes involved in these mechanisms of control are essential to our understanding of the mammalian developmental processes. The embryonic expression pattern of many oncogenes acting as transcriptional factors suggests a role for these genes in mammalian development. In our laboratory, we have previously shown that the oncogene and transcriptional factor N-myc is essential for normal mammalian development. The N-myc function might involve the amplification of precursor cells by promoting their growth, inhibiting their death, and controlling their terminal differentiation. Therefore, the characterization of the mechanisms of regulation of N-myc is a critical step for our understanding of the processes of cell growth and differentiation. In the present application, we propose to examine the requirements for the appropriate regulation of N-myc gene expression during mouse embryogenesis in order to determine the molecular mechanisms responsible for the N-myc restricted domains of expression. Overall, the experiments proposed constitute a comprehensive approach combining genetic, molecular and biochemical analyses that should provide invaluable information on the mechanisms involved in the regulation of this important oncogene.