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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052309-03
Application #
2685050
Study Section
Biological Sciences 2 (BIOL)
Project Start
1996-04-09
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Hoffmann, B; Zuo, W; Liu, A et al. (2001) The LIS1-related protein NUDF of Aspergillus nidulans and its interaction partner NUDE bind directly to specific subunits of dynein and dynactin and to alpha- and gamma-tubulin. J Biol Chem 276:38877-84
Han, G; Liu, B; Zhang, J et al. (2001) The Aspergillus cytoplasmic dynein heavy chain and NUDF localize to microtubule ends and affect microtubule dynamics. Curr Biol 11:719-24
Ahn, C; Morris, N R (2001) Nudf, a fungal homolog of the human LIS1 protein, functions as a dimer in vivo. J Biol Chem 276:9903-9
Dawe, A L; Caldwell, K A; Harris, P M et al. (2001) Evolutionarily conserved nuclear migration genes required for early embryonic development in Caenorhabditis elegans. Dev Genes Evol 211:434-41
Xiang, X; Han, G; Winkelmann, D A et al. (2000) Dynamics of cytoplasmic dynein in living cells and the effect of a mutation in the dynactin complex actin-related protein Arp1. Curr Biol 10:603-6
Morris, N R (2000) Nuclear migration. From fungi to the mammalian brain. J Cell Biol 148:1097-101
Efimov, V P; Morris, N R (2000) The LIS1-related NUDF protein of Aspergillus nidulans interacts with the coiled-coil domain of the NUDE/RO11 protein. J Cell Biol 150:681-8
Dawe, A L; Willins, D A; Morris, N R (2000) Increased transformation efficiency of Aspergillus nidulans protoplasts in the presence of dithiothreitol. Anal Biochem 283:111-2
Liu, B; Morris, N R (2000) A spindle pole body-associated protein, SNAD, affects septation and conidiation in Aspergillus nidulans. Mol Gen Genet 263:375-87
Aist, J R; Morris, N R (1999) Mitosis in filamentous fungi: how we got where we are. Fungal Genet Biol 27:1-25

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