Worm Breeder's Gazette 11(2): 46
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.
The accompanying figure shows sequence alterations associated with eight lin-12(d) alleles. All eight lin-12(d) mutations examined are missense alterations of the protein coding region and are therefore likely to be modifying protein activity or increasing protein stability. Thus, the fact that lin-12(d) mutations behave like genetic hypermorphs (Greenwald et al., Cell 34: 435 -444,1983) would be consistent with two possibilities: either the lin-12(+) allele contributes a basal level of lin-12 activity that can augment lin-12(d) activity, or the lin-12(d) protein transactivates the lin-12(+) protein. We favor the second possibility, in light of genetic studies suggesting that lin-12 interacts with itself (Geraldine Seydoux and I. G., unpublished observations) and biochemical evidence that Notch can form dimers (Kidd et al., Genes & Dev. 3:1113-1129,1989). Our current favorite working hypothesis is that intercellular signals promote self-association of lin-12, thereby activating a signal transduction mechanism. This model is plausible in view of what is known about biochemically-defined receptors: in many cases, the association state of receptors in the membrane controls their activity, and association state is in turn controlled by ligand-binding ( reviewed in Andersen, Nature 337:12,1989). The lin-12(d) mutations could lead to activation in the absence of signals necessary to activate lin12(+) protein. Consistent with this explanation is the observation that if all gonadal cells except for Z1.ppp or Z4.aaa are ablated in a lin-12(n137) hermaphrodite, it becomes a VU; in contrast, in wild type, it would become an AC, presumably because it lacks a necessary signal (Seydoux and Greenwald, Cell 57:1237-1245,1989). [See Figure 1] Predicted amino acid changes (residue number: change) deduced from sequence analysis of different lin-12(d) alleles are shown on a schematic depiction of the lin-12 product (Yochem et al., Nature 335: 547-550,1988). EGF = EGF-like motifs; T = 'T + Y' encoded motif; LNR = lin12/Notch repeated motif; cdc10 = cdc10/SWI6 motif; C = position of a pair of cysteines that is conserved in lin-12, h. Kidd et al. (1989) propose that these cysteines mediate the dimerization of Notch, and it is curious that they are conserved in a region of the lin-12 protein that shows no overt sequence similarity to Notch.