The aim of this work is to understand the timing mechanisms that govern specific cell fate decisions during development. Genetic and molecular methods will be used to dissect the mechanism that restricts the terminal differentiation of lateral hypodermal """"""""seam"""""""" cells to the final molt in nematode C. elegans. At that time, the seam cells exit the proliferative larval seam cell program and execute the adult terminal differentiation program, a process called the larval-to-adult switch (L/A switch). The transcription factor LIN-29 is the most direct known regulator of the L/A switch, and its activity is timed by the heterochronic genes lin-4, lin-14, and lin- 28. The genes lin-4, line-14, lin-28 and lin-29 are not the complete set of regulators that time seam cell terminal differentiation. Genetic screens will be used to identify additional genes that time the L/A switch. These screens have already identified lin-42 as an additional important temporal regulator. Genetic and molecular analysis of lin-42, and other newly identified heterochronic genes, will be performed to determine their roles in the timing pathway. When worms reinitiate development following the developmentally-arrested """"""""dauer larva"""""""" stage the suspends the continuous timing program and the L/A switch must be rescheduled in the post-dauer worm. Genetic screens will be performed to test if there are genes that time lin-29 activity specifically during post-dauer development. The molecular mechanism by which the upstream genes control the timing of lin-29 activity will be determined. Sequences critical for lin-29 regulation will be defined by transformation rescue and the patterns of accumulation of lin-29 gene products will be determined. Lin-29 activity is also required for proper vulva formation during the L4 molt. Whether this requirement reflects a role for lin-29 in vulva/somatic gonad cells and/or in the surrounding hypodermis will be tested by mosaic analysis. Loss of lin-29 function causes cells of the adult stage to indefinitely reiterate the larval program of cell divisions instead of exciting the cell cycle and differentiating. Thus, lin-29 can be thought of in general terms as an anti-oncogene: a gene whose function is required for cell cycle exit. Temporal control of lin-29 thus 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 our 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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