Worm Breeder's Gazette 12(1): 34 (September 1, 1991)

These abstracts should not be cited in bibliographies. Material contained herein should be treated as personal communication and should be cited as such only with the consent of the author.

lin-3 encodes a TGFalpha like molecule which may act as a AC signal that induces vulval development.

Russell Hill, Paul Sternberg

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Division of Biology, Caltech. Pasadena, CA 91125.

lin-3 is required for vulval induction and acts in a pathway upstream of let-60 ,which encodes a ras protein, and of let-23 ,which encodes a homolog of the EGF receptor (EGF-R). Preliminary genetic and molecular data suggest that lin-3 may be a signal made by the anchor cell which induces vulval development.

Whereas reduction of lin-3 activity causes a recessive vulvaless (Vul) phenotype, multicopy lin-3 transgenes cause a dominant multivulva (Muv) phenotype. Two experiments using these transgenes are consistent with the hypothesis that lin-3 acts as an inductive signal. First, the Vul mutation let-23 ( sy97 )is epistatic to the Muv phenotype of the lin-3 transgene syEx13 .Thus presumptive overexpression of lin-3 by a transgene can only stimulate vulval fates if let-23 is functional. This observation suggests that the role of lin-3 is to activate let-23 .Second, the Muv phenotype of the lin-3 transgene syEx13 is dependent upon the gonad. Ablation of the gonad precursors in L1 syEx13 animals causes these animals to be Vul. Thus the transgenic animals either make lin-3 in the gonad, or lin-3 is made elsewhere but requires the gonad to be activated.

lin-3 encodes a transmembrane protein with a single EGF repeat, which is a structural motif found in a wide variety of proteins. Based on the overall structure of lin-3 ,we believe that lin-3 belongs to the family of growth factors that includes Transforming Growth Factor alpha (TGFalpha) and other known ligands of the mammalian EGF-R. Such molecules are made as membrane bound proforms that contain one or more EGF repeats. The membrane proximal EGF repeat is the ligand that is often proteolytically processed to create a secreted signal. In at least some cases, though, the membrane bound form also can activate the receptor. lin-3 requires the EGF repeat to function. The introduction of mutations into the transgenes that convert the third and fifth cysteines of the EGF repeat to serines results in a transgene with no ability to rescue a lin-3 Vul mutation or to cause a dominant Muv phenotype. Transgenes possessing either single mutation retain some function.

We propose that lin-3 is a vulval inducing signal that acts through the EGF-R homolog let-23 .We are currently investigating whether lin-3 is a ligand of let-23 ,whether lin-3 is processed to create a secreted form, whether the membrane form has activity, and where lin-3 is expressed.

[See Figure 1]

Figure 1