Aroian, Raffi V (1992) The let-23 gene of the nematode C. elegans : genetics and molecular biology of a member of the EGF receptor tyrosine kinase family. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:09142011-114200593
Genetic studies indicate that the let-23 gene affects several developmental decisions in the nematode Caenorhabditis elegans. let-23 is required for the proper development of the hermaphrodite vulva, the male tail, and the posterior ectoderm. In addition, let-23 mutations can cause lethality and hermaphrodite sterility. These five let-23 functions can be independently mutated, suggesting that the let-23 protein encodes tissuespecific functions . Furthermore, let-23 controls two opposing pathways: one that stimulates and another that inhibits vulval development. These two pathways ensure that the proper level of vulval development occurs. Twenty let-23 alleles exist: 14 eliminate function (null), three reduce function in all tissues (hypomorphic), and three reduce function in certain tissues (tissue-specific). In addition, two of these alleles are defective in the inhibitory vulval pathway.
The let-23 primary structure resembles that of the mammalian epidermal growth factor receptor (EGFR). The let-23 protein possesses putative ligand binding, transmembrane, and tyrosine kinase domains, as well as cysteine-rich regions, all with the characteristics of the EGFR family. Like let-23, mammalian EGFR is multifunctional, encodes tissuespecific functions, and functions in stimulatory and inhibitory pathways. let-23 may be the receptor in the vulva for the anchor-cell inductive signal. Furthermore, genetic data indicate let-23 acts upstream of the let-60 ras gene, supporting mammalian studies that suggest a link between EGFR and ras.
To investigate how EGFR primary structure relates to function, mutations in eight let-23 alleles have been sequenced. Five null alleles alter sequences in both the kinase and the extracellular domains. These alterations suggest that let-23 has kinase activity and that the extra cysteine domain found only in invertebrate EGFRs is important. A strong hypomorphic allele mutates one of the conserved extracellular cysteines close to the ligand binding domain. A tissue-specific allele mutates an intronlexon boundary in the C-terminus. This mutation suggests that the C-terminus can provide tissue-specific information. Finally, a hypomorphic allele that is defective in the let•23 inhibitory vulval pathway alters a different intron/exon boundary in the C-terminus. This mutation results in numerous, unexpected transcripts. Models are suggested to account for the behavior of this allele.
|Item Type:||Thesis (Dissertation (Ph.D.))|
|Degree Grantor:||California Institute of Technology|
|Thesis Availability:||Restricted to Caltech community only|
|Defense Date:||25 November 1991|
|Default Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Dan Anguka|
|Deposited On:||15 Sep 2011 17:40|
|Last Modified:||26 Dec 2012 04:38|
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