Morphogenesis is a process used throughout development in the generation of many tissues and organs. Morphogenesis is also extremely important for medical reasons, including wound healing, nervous system regeneration and cancer metastasis. During morphogenetic events, cells must interpret positional information from the external environment, and subsequently act upon that information by altering cytoskeletal dynamics. The study of morphogenesis using C. elegans genetics has been fruitful, particularly in development of the nervous system, whose function is largely dispensable in the laboratory. However, essential genes exist that are involved more generally in morphogenetic events, including early formation of the embryo and organogenesis, and only rare viable alleles in this class would have been identified in most screens. Since transmembrane receptors can function in both signal transduction and adhesion, we reasoned that novel receptors are good candidates for unknown and essential components of morphogenesis. We noticed that there are several receptor tyrosine kinases (RTKs) in the worm genome that have atypical or novel extracellular domains without the distinctive sequence motifs characteristic of growth factor receptors. These extracellular domains probably bind novel ligands, perhaps components of the extracellular matrix or other positional cues. We studied six such receptors and found that over-expression of 5 of the 6 caused lethality, at least some of which is probably due to gross hypodermal morphology defects. RNAi of 4 of 6 genes also caused apparent defects in morphogenesis. Our observations support our basic hypothesis, and we have chosen two genes for further study. T10H9.2 encodes an RTK with extensive similarity in the kinase domain to the human Leukocyte Tyrosine Kinase and Anaplastic Lymphoma Kinase RTKs, whose functions are unknown. Some extracellular motifs that may mediate protein-protein interactions are still present in both, but appear more diverged than the cytoplasmic domains. Over-expression of T10H9.2 causes lethality, probably due to morphogenetic defects, and RNAi causes variable gross morphological and nervous system defects, including wandering axons and defasciculation. We constructed a deletion library, have isolated two deletion alleles in this gene, and are proceeding to characterize them. T14E8.1 encodes an RTK that is similar to the human HGF Receptor/c-met proto-oncogene in the cytoplasmic domain, but has a novel ectodomain. T14E8.1 may be encoded by mab-19 , a gene originally characterized by Sutherlin and Emmons (Genetics 138: 675). Though we have not found the DNA lesions corresponding to the two mab-19 alleles, four lines of evidence support the model that T14E8.1 is encoded by mab-19 : mab-19 maps to a very small physical interval containing the RTK, a PCR product of T14E8.1 alone rescues the Mab phenotypes, a T14E8.1 RNA-foldback construct driven by the hsp-16-2 promoter causes Mab phenotypes similar to those of mab-19 , and a T14E8.1 promoter::GFP construct is expressed in several cell types in the animals, including a subset of male tail sensory rays. Emmons and Sutherlin found that mab-19 / Df caused embryonic lethality, suggesting that the two alleles are hypomorphic. The lethality appears to be due to failure of the dorsal hypodermis to migrate ventrally and enclose the animal. Our deletion library will be screened for null alleles of T14E8.1.