To understand how programmed cell death is regulated during development, we are studying mechanisms that determine the pattern of programmed cell deaths in the ventral cord. In the midbody the six Pn.aap cells survive and differentiate to form VC motor neurons, while lineally-equivalent cells in the anterior and posterior die. Through two genetic screens we have found that
unc-3 and
pag-3 mutants have both extra cell corpses and extra VC motor neurons in the ventral cord. In
pag-3 mutants these phenotypes are a consequence of a P cell lineage defect wherein the Pn.aaa neuroblast reiterates the fate of its mother, Pn.aa, to generate extra Pn.aap cells, some of which live and some of which die. Analysis of the number of Pn.aap cells in
unc-3 pag-3 double mutants suggests that
unc-3 and
pag-3 may function together to determine the number of Pn.aap cells. This functional interaction is not obligatory in all cells as
unc-3 pag-3 mutants, but neither single mutant, are Mec, suggesting redundant functions, and
unc-3 functions without
pag-3 to prevent dauer-formation at 27oC. UNC-3 and PAG-3 are coexpressed in ventral cord motor neurons. Our finding of similar phenotypes in the ventral cord of
pag-3 and
unc-3 mutants prompted us to ask whether mammalian homologues of
pag-3 and
unc-3, the Gfi-1 and O/E genes respectively, might also function together to promote particular cell fates. Gfi-1 and O/E-1 are known to be coexpressed in hematopoietic cells, and O/E-1 is required for development of the B cell lineage in mice. Gfi-1 may directly regulate apoptosis. The O/E-1 protein is known to physically interact with a C2H2 Zn-finger protein ROAZ, suggesting the possibility that PAG-3, which encodes a C2H2 Zn-finger protein, might interact directly with UNC-3 in the ventral cord to specify Pn.aaa neuroblast fate and/or to regulate terminal neuronal fates, including programmed cell death, and that a Gfi-1 protein might interact with an O/E protein in hematopoietic cells. We are currently testing these ideas.