The overall goal of this proposal is to elucidate the mechanisms of animal development rough the study of the nematode Caenorhabditis elegans, a model organism chosen for its relative cellular simplicity and its advantages for classical and molecular genetic analysis. An understanding of the genetic basis of development may well be fundamental to much of medicine and may ultimately contribute important information to many problems, ranging from congenital defects to senescence.
Five specific aims are proposed. The long-term objective of the first four specific aims is to identify and characterize the molecular mechanisms of action of a large network of genes that interact, directly or indirectly, with the C. elegans mec-8 gene, which encodes a protein with two RNA recognition motifs and regulates the processing of transcripts of several genes, including unc-52. Besides using genetic approaches to expand a gene network, methods for studying genetic redundancy in C. elegans are introduced. The first specific aim is to identify and characterize mutations that are synthetic lethal with mec-8 loss-of-function mutations. Such mutations, called sym for synthetic lethal with mec-8, define genes that functionally overlap mec-8. Mutations in sym genes by themselves confer essentially no mutant phenotype but in combination with a mec-8 mutation are lethal.
The second aim i s to identify by mutation additional genes that interact with sym-1, which encodes a protein that is secreted from the apical surface of the embryonic hypodermis and plays a role in the attachment of body muscle to cuticle. Mutations that are synthetic lethal with a sym-1 mutation will be sought, as will suppressors of the synthetic lethality of mec-8 and sym-1 mutations. The third specific aim is to identify and characterize molecularly several of the genes that interact with mec-8. Four such genes have already been defined genetically; others will be identified under the first two specific aims. The fourth specific aim is to characterize the effects of mec-8 and two other genes, defined by mutations that suppress mec-8 mutations, on the processing of unc-52 pre-mRNA. The long-term objective of the fifth specific aim is to learn more about the assembly and maintenance of eukaryotic cilia and flagella. Mutations to ten C. elegans genes that affect the ability of living animals to incorporate a fluorescent dye into a set of sensory neurons will be characterized further in order to identify those genes that affect assembly of sensory cilia. Null alleles of such genes will be sought.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM022387-28S1
Application #
6918257
Study Section
Genetics Study Section (GEN)
Program Officer
Haynes, Susan R
Project Start
1976-03-01
Project End
2006-01-31
Budget Start
2003-03-01
Budget End
2006-01-31
Support Year
28
Fiscal Year
2004
Total Cost
$89,538
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Genetics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Yochem, John; La┼żeti?, Vladimir; Bell, Leslie et al. (2015) C. elegans NIMA-related kinases NEKL-2 and NEKL-3 are required for the completion of molting. Dev Biol 398:255-66
Bell, Leslie R; Stone, Steven; Yochem, John et al. (2006) The molecular identities of the Caenorhabditis elegans intraflagellar transport genes dyf-6, daf-10 and osm-1. Genetics 173:1275-86
Yochem, John; Hall, David H; Bell, Leslie R et al. (2005) Isopentenyl-diphosphate isomerase is essential for viability of Caenorhabditis elegans. Mol Genet Genomics 273:158-66
Spartz, Angela K; Herman, Robert K; Shaw, Jocelyn E (2004) SMU-2 and SMU-1, Caenorhabditis elegans homologs of mammalian spliceosome-associated proteins RED and fSAP57, work together to affect splice site choice. Mol Cell Biol 24:6811-23
Yochem, John; Bell, Leslie R; Herman, Robert K (2004) The identities of sym-2, sym-3 and sym-4, three genes that are synthetically lethal with mec-8 in Caenorhabditis elegans. Genetics 168:1293-306
Spike, Caroline A; Davies, Andrew G; Shaw, Jocelyn E et al. (2002) MEC-8 regulates alternative splicing of unc-52 transcripts in C. elegans hypodermal cells. Development 129:4999-5008
Spike, C A; Shaw, J E; Herman, R K (2001) Analysis of smu-1, a gene that regulates the alternative splicing of unc-52 pre-mRNA in Caenorhabditis elegans. Mol Cell Biol 21:4985-95
Davies, A G; Spike, C A; Shaw, J E et al. (1999) Functional overlap between the mec-8 gene and five sym genes in Caenorhabditis elegans. Genetics 153:117-34
Herman, M A; Ch'ng, Q; Hettenbach, S M et al. (1999) EGL-27 is similar to a metastasis-associated factor and controls cell polarity and cell migration in C. elegans. Development 126:1055-64
Lundquist, E A; Herman, R K; Shaw, J E et al. (1998) UNC-115, a conserved protein with predicted LIM and actin-binding domains, mediates axon guidance in C. elegans. Neuron 21:385-92

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