Epidermal morphogenesis underlies much of animal development, yet the molecular mechanisms of epithelial movements are still poorly understood. We study the epidermis of the nematode Caenorhabditis elegans as a simple model for many aspects of epithelial morphogenesis. Our long-term goal is to identify the proteins that regulate epidermal morphogenesis. We have identified genes that function in neuronal cell signaling to regulate C. elegans epidermal morphogenesis. These include an Eph receptor tyrosine kinase (VAB-1), an ephrin ligand 3. Our genetic analysis showed that Eph signaling forms part of a network of partly redundant for the VAB-1 receptor (EFN-l/VAB-2), and the LAR-type receptor tyrosine phosphatase PTP- signaling pathways that regulate C. elegans morphogenesis. We will analyze how Eph signaling functions to regulate cell behaviors in morphogenesis, both to better understand the mechanisms of Eph signaling pathways and to elucidate their in vivo function in morphogenesis. We have three specific aims. (1) We will characterize a divergent C. elegans ephrin, EFN-4. Mutations in EFN-4 affect morphogenesis. We will test whether EFN-4 is a ligand with the VAB-1 receptor and whether it modulates effects of other C. elegans ephrins. We will also search for novel EFN-4 binding proteins. (2) Our earlier work showed that Eph signaling function is partly redundant with two other pathways. In screens to identify new components of such pathways, we have identified a locus that shows synthetic-lethal interactions with vab-1. To better understand the pathways that interact with Eph signaling we will characterize this gene and identify other vab-1-interacting genes. (3) Suppressor analysis can identify components of signaling pathways that may not be found by direct genetic screens. We have identified suppressors of vab-1 loss-of-function mutations and will analyze one of these suppressors genetically and by molecular cloning. We will also generate gain-of-function (constitutively activated) versions of VAB-1 and use these in new suppressor screens. Eph signaling plays many roles in neural and vascular development and has been implicated in tumorigenesis.
These aims take advantage of genetic approaches available in C. elegans to study Eph signaling and its roles in neural and epidermal morphogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054657-09
Application #
6872877
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Haynes, Susan R
Project Start
1997-05-01
Project End
2006-12-31
Budget Start
2005-05-01
Budget End
2006-12-31
Support Year
9
Fiscal Year
2005
Total Cost
$275,672
Indirect Cost
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Mulcahy, Ben; Witvliet, Daniel; Holmyard, Douglas et al. (2018) A Pipeline for Volume Electron Microscopy of the Caenorhabditis elegans Nervous System. Front Neural Circuits 12:94
E, Lezi; Zhou, Ting; Koh, Sehwon et al. (2018) An Antimicrobial Peptide and Its Neuronal Receptor Regulate Dendrite Degeneration in Aging and Infection. Neuron 97:125-138.e5
Gotenstein, Jennifer R; Koo, Cassidy C; Ho, Tiffany W et al. (2018) Genetic Suppression of Basement Membrane Defects in Caenorhabditis elegans by Gain of Function in Extracellular Matrix and Cell-Matrix Attachment Genes. Genetics 208:1499-1512
Chen, Fei; Chisholm, Andrew D; Jin, Yishi (2017) Tissue-specific regulation of alternative polyadenylation represses expression of a neuronal ankyrin isoform in C. elegans epidermal development. Development 144:698-707
Xu, Suhong; Wang, Zhiping; Kim, Kyung Won et al. (2016) Targeted Mutagenesis of Duplicated Genes in Caenorhabditis elegans Using CRISPR-Cas9. J Genet Genomics 43:103-6
Chuang, Marian; Hsiao, Tiffany I; Tong, Amy et al. (2016) DAPK interacts with Patronin and the microtubule cytoskeleton in epidermal development and wound repair. Elife 5:
Venkatachalam, Vivek; Ji, Ni; Wang, Xian et al. (2016) Pan-neuronal imaging in roaming Caenorhabditis elegans. Proc Natl Acad Sci U S A 113:E1082-8
Chisholm, Andrew D; Hutter, Harald; Jin, Yishi et al. (2016) The Genetics of Axon Guidance and Axon Regeneration in Caenorhabditis elegans. Genetics 204:849-882
Xu, Suhong; Chisholm, Andrew D (2016) Highly efficient optogenetic cell ablation in C. elegans using membrane-targeted miniSOG. Sci Rep 6:21271
Schwieterman, Alicia A; Steves, Alyse N; Yee, Vivian et al. (2016) The Caenorhabditis elegans Ephrin EFN-4 Functions Non-cell Autonomously with Heparan Sulfate Proteoglycans to Promote Axon Outgrowth and Branching. Genetics 202:639-60

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