Control of developmental time is of fundamental importance to all multicellular organisms and is achieved with astonishing precision.
The aim of this work is to understand the timing mechanisms that govern specific cell fate decisions during metazoan development, using the nematode C. elegans as a model organism. The heterochronic genes of C. elegans are global temporal regulators that control the sequence and timing of diverse events during postembryonic development. Mutations in these genes alter the relative timing of developmental programs, causing certain events to occur too early or too late. This research will primarily investigate the molecular roles of three key temporal regulatory genes: lin-58, lin-42, and hbl-1. Emphasis will be directed at understanding how these genes receive temporal information from genes acting upstream in the hierarchy and in turn relay that information to correctly time expression of downstream targets, lin-58 mutations define temporal regulatory role for the mir-48 microRNA, which acts early in development, while lin-42 and hbl-1 are distinct in that their analysis reveals both early and late roles suggesting they have a more global timing function. Molecular mechanism(s) of action of these genes will be determined, including analysis of conserved homology domains, and they will be positioned with respect to others in the pathway through genetic analysis. A key goal is to identify molecules that interact directly with the products of these genes and to determine their function. A variety of molecular and biochemical techniques will be employed to achieve this aim. Genetic screens will identify additional temporal regulatory genes. Relevance to human health: Understanding the mechanisms by which these genes act provides a model for how cells within an organism are instructed to cease dividing at a specific time in development and differentiate. Knowledge about this control should aid in the understanding of the problems that occur when growth controls go awry, such as the inappropriate resumption of cell divisions that occurs in some cancers.
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