CYTOPLASMIC DYNEIN STRUCTURE AND FUNCTION

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Intracellular nuclear migration plays an important role in eukaryotic development. Because nuclear migration into the mycelium is particularly conspicuous in fungi and is required for fungal growth and development, the filamentous fungus Aspergillus nidulans was used as a model system to identify molecules involved in nuclear migration. A set of temperature sensitive nud (nuclear distribution) mutants was identified in which intracellular nuclear migration is defective. Two of these mutants, nudA and nudG, encode components of a molecular motor, the cytoplasmic dynein heavy and light chains respectively. This identified cytoplasmic dynein as the main motor responsible for nuclear migration in A. nidulans. Preliminary work localized cytoplasmic dynein to the growing tip of the mycelium, and plans are presented for determining whether this is the dynein that actually moves the nucleus. Two other nud genes, nudF and nudC, are unique because they encode proteins that are not components of either dynein or its dynactin activator. nudF encodes a WD40 protein similar to the beta-subunit of the heterotrimeric G proteins. Among this family of proteins, it most closely resembles (42% identity) a gene, LIS- 1, that is defective in patients with lissencephaly, a disease in which the brain fails to develop properly. nudC regulates dynein function indirectly by posttranscriptionally controlling the level of nudF protein in the cell. Other nud mutations remain to be characterized. This grant includes plans for the identification of additional genes that are important for nuclear migration by identification of new migration defective strains; by analysis of extragenic suppressors of several of the nud mutations; and by biochemical analyses of dynein function in mutant strains.