Worm Breeder's Gazette 13(4): 62 (October 1, 1994)

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.

Unknown pathways: signal transduction from the daf-4 receptor ser/thr kinase.

David Gems and Don Riddle

Division of Biological Sciences, University of Missouri, Columbia, MO 65211

     Dauer larva formation involves a complex signaling pathway
initiated by chemosensation in the amphid neurons, and ending in changes
in gene expression throughout the organism. Several genes, daf-1, daf-4 and
daf-7, which promote non-dauer development, encode cell-surface receptors
or ligands of the TGF-beta superfamily. Members of this superfamily are
involved in many aspects of growth and development in mammals, frogs
and flies - e.g. body plan specification in early embryogenesis, control of 
limb, bone, cartilage, neural tube and sexual organ formation, immune and
endocrine functions and so on. How signals are transduced from
TGF-beta-like receptors to the nucleus is unknown. By contrast, the
sem-5/let-60/lin-45/mpk-1 or sur-1 vulval induction pathway involved in
signal transduction from the EGF-type  let-23 tyrosine kinase receptor 
is well characterized (1). 

     We wanted to know whether components of the vulval induction
pathway are involved in signal transduction from the daf-4 receptor (2).
Double mutants were made using a weak daf-4 mutation, m592, and
sem-5(n1779), let-60(s59lf), let-60(n1046gf), lin-45(sy96) and 
mpk-1(n2521) (thanks to Paul Sternberg and Stuart Kim for sending strains).
At 22.5oC, m592 causes a small adult body size (Sma) phenotype, and at
25oC forms >90% dauer larvae (Daf-c). Double mutants were tested for
enhancement or suppression of Daf-c or Sma.  None of the let-23 pathway
mutants had any substantial effect on the Daf-c phenotype. However,
let-60(gf) did enhance the Sma phenotype, perhaps by activating a 
function antagonistic to daf-4 in its body size-determining capacity. let-60(gf)
does not have any detectable effect on the daf-4(m592)  male tail defects
(Scott Baird, personal communication). These results suggest that TGF-beta
receptors transduce signals to the nucleus via a distinct pathway of signaling
components. Given the conservation of the EGF signaling pathway between
yeast, Caenorhabditis, Drosophila and mammals, this result may 
prove to be general to receptors for TGF-beta family ligands. We have not
yet studied more severe alleles  of sem-5 or mpk-1/sur-1, or a dominant
negative mutant allele of let-60.

      Interaction between daf-4(m592) and unc-101(m1) was also
examined. unc-101 mutations suppress a hypomorphic allele of let-23,
possibly the result of abnormal trafficking of the LET-23 receptor causing an
an increase in its effective activity (3). Here, however, some enhancement of
Daf-c was observed. This could reflect a functional property of the
daf-4(m592) receptor, or, as is more likely, a synergistic effect on the
function of the neurons which control dauer development since unc-101(m1)
causes ciliary abnormalities in amphid sensory neurons (Hall and
Hedgecock, WBG 11 -1: 56).

(1)  Sternberg, Ann. Rev. of Genet. 27 497-520, 1993.
(2)  Estevez et al., Nature 365 644-649, 1993.
(3)  Lee et al., Genes and Dev. 8 60-73, 1994.