The proposed research will continue our efforts to define the roles of the genetic elements which specify muscle assembly in the nematode Caenorhabditis elegans. The advances made in the past grant period both in our own work and elsewhere make available a variety of powerful approaches to isolate genes and to study their roles in C. elegans. We shall exploit this knowledge base to study critical aspects of thick and thin filament assembly and we shall continue roles in muscle development. The myosin heavy chain sequences which allow the initiation of myosin assembly and the proteins with which they interact in the assembly process will be defined. The genes unc-87, unc-82, and unc-89 will be analysed to determine if they encode either minor components which play important parts in thick filament, somehow direct its assembly. The proteins vinculin and capZ are likely to have a role in initiating thin filament formation and positioning thin filaments within the cell. Vinculin mutants will be used to determine with which proteins it interacts and to study specific mutations of the gene to learn more about functions of the molecule. The genes for the capZ subunits will be identified and combined molecular genetic approaches used to define its role. Four other genes, unc-60, unc-78, unc-94 and unc-95, likely to have important functions in thin filament assembly will be studied through molecular and genetic studies. Whether these genes encode proteins that become incorporated into the lattice or instead direct its assembly by modifying its components will be ascertained. A class of new, essential muscle genes has been defined in the past grant period. We will collect additional mutants of this class, and describe the phenotypes of members of the class in more detail. We will focus our attention on a small number of these genes for more detailed molecular and genetic studies. These genes may encode additional components of the myofilament lattice or involve other aspects of muscle development. We shall also clone the nematode dynein heavy chain gene and use a combined molecular and genetic approach to determine its role in cell division and cell morphogenesis during development. By defining the role of these genes and identifying yet new ones, we will begin to learn the principles by which the genome specifies muscle structure in development, not only in the nematode, but in all higher organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM023883-18
Application #
2174168
Study Section
Genetics Study Section (GEN)
Project Start
1977-04-01
Project End
1995-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
18
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Washington University
Department
Genetics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
De Vit, M J; Waddle, J A; Johnston, M (1997) Regulated nuclear translocation of the Mig1 glucose repressor. Mol Biol Cell 8:1603-18
Liu, J; Schrank, B; Waterston, R H (1996) Interaction between a putative mechanosensory membrane channel and a collagen. Science 273:361-4
Waddle, J A; Karpova, T S; Waterston, R H et al. (1996) Movement of cortical actin patches in yeast. J Cell Biol 132:861-70
Williams, B D (1995) Genetic mapping with polymorphic sequence-tagged sites. Methods Cell Biol 48:81-96
Waddle, J A; Cooper, J A; Waterston, R H (1994) Transient localized accumulation of actin in Caenorhabditis elegans blastomeres with oriented asymmetric divisions. Development 120:2317-28
Williams, B D; Waterston, R H (1994) Genes critical for muscle development and function in Caenorhabditis elegans identified through lethal mutations. J Cell Biol 124:475-90
Goetinck, S; Waterston, R H (1994) The Caenorhabditis elegans muscle-affecting gene unc-87 encodes a novel thin filament-associated protein. J Cell Biol 127:79-93
Goetinck, S; Waterston, R H (1994) The Caenorhabditis elegans UNC-87 protein is essential for maintenance, but not assembly, of bodywall muscle. J Cell Biol 127:71-8
Waddle, J A; Cooper, J A; Waterston, R H (1993) The alpha and beta subunits of nematode actin capping protein function in yeast. Mol Biol Cell 4:907-17
Williams, B D; Schrank, B; Huynh, C et al. (1992) A genetic mapping system in Caenorhabditis elegans based on polymorphic sequence-tagged sites. Genetics 131:609-24

Showing the most recent 10 out of 22 publications