Nuclear migration through the cytoplasm occurs in organisms from fungi to man and is required for the growth and proper development of most eukaryotes. Our laboratory has been studying the molecular genetics of nuclear migration in a simple eukaryote, the filamentous fungus Aspergillus nidulans. To date we have identified fourteen """"""""nud"""""""" (nuclear distribution) genes whose products are involved in nuclear migration and have cloned and characterized seven of them. All are evolutionarily conserved. Some are components of the molecular motor cytoplasmic dynein. Others are components of dynactin, a protein complex thought to couple the dynein motor to membrane-bounded cargo. Still other nud gene products are components of neither dynein or dynactin, but presumably are proteins that play a regulatory or as yet unknown structural role in nuclear migration. One of these nud gene products, NUDF, is particularly fascinating because a deficiency of its human homolog, LIS 1, causes lissencephaly, a genetic disease in which neurons fail to migrate properly from the paraventricular proliferative zone of the brain to the cerebral cortex. Because nuclear migration occurs in neurons and has been described to be an important component of cell migration in certain cancer cells that undergo nucleokinesis, we have proposed that the failure of neuronal migration in lissencephaly is really a failure of nuclear migration. Evidence from a LIS 1 knockout mouse supports this conclusion. The main thrust of this application is to determine how the NUDF protein affects nuclear migration by analyzing its effects on the function of the cytoplasmic dynein motor, the dynactin coupling machinery, and on the microtubule track with which the motor interacts in vivo and in vitro, using wild-type and nud mutant strains of Aspergillus.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052309-06
Application #
6386125
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Deatherage, James F
Project Start
1996-04-09
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
6
Fiscal Year
2001
Total Cost
$345,400
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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