Worm Breeder's Gazette 13(5): 30 (February 1, 1995)

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.

Genes Regulating Muscle Activation (Mac).

David J. Reiner, David Weinshenker, James H. Thomas

Department of Genetics, SK-50, University of Washington, Seattle, WA 98195

We have analyzed a large number of genes that we believe
act in muscle activation (Mac). Here we describe mutations
that are muscle activation-defective (Mac-d) and muscle
hyper-activated (Mac-h). Mutations in the following
genes are Mac-d: egl-2, egl-l9, egl-23, egl-30, egl-36,
exp-2, exp-3, exp-4, unc-93, sup-9, sup-10, and unc-103.
Our main criterion for this group is phenotypic similarity
to muscle structure mutants (e.g. unc-54), with the exception
that Mac mutants generally display more ability for muscle
contractility. This point is best illustrated by an archetypal
Mac-d mutation, unc-93(el500sd). el500sd mutant animals
are "rubber-band" Uncs: they are flaccidly paralyzed
and slightly long, similar to unc-54 mutants. Unlike unc-54
mutants, they respond to touch by strong contraction of
the body-wall muscles followed promptly by relaxation.
unc-93(el500sd) also confers a strong Egl defect, and
a strong Exp (defecation) defect. Several Mac-d mutations
do not cause Unc defects, but have Egl and Exp defects like
unc-93. We have shown that all Mac-d mutations affecting
egg-laying are resistant to serotonin and levamisole
induction of egg-laying, suggesting post synaptic defects.
Mac-h mutants are Egl-c and Dpy. The genes unc-58, unc-90,
unc-105, and eat-12 (a.k.a. egl-l9) belong to this functional
group. We have shown that the Dpy and Egl-c phenotypes of
all Mac-h mutants are suppressed by mutations in unc-54,
indicating that the Dpy and Egl-c phenotypes are caused
by hyper-contracted body-wall and egg-laying muscle,
All 15 of these Mac-d and Mac-h genes share genetic characteristics.
The Mac-d and Mac-h phenotypes in each case are caused by
semi-dominant mutations. In addition, of the eleven Mac
genes for which loss-of-function mutations have been
isolated, all but one of them have a grossly wild-type loss-of-function
phenotype. We propose that the Mac-d and Mac-h genes function
in the process of regulation of muscle excitation. We deem
it unlikely that these genes are involved in the primary
excitatory signal for muscle contraction, since l) most
of these genes are not essential for muscle contraction,
and 2) they affect multiple pharmacologically-distinct
muscle types, suggesting that they encode components
common to different muscles. We hypothesize that such
components could be ion channels that modulate the basal
excitability of muscle cells, regulatory signal transduction
pathways that respond to modulatory neurotransmitters,
or feedback or adaptation pathways.
We have found that two additional genes, unc43 and unc-ll0,
appear to act in the Mac process. Both are defined by semi-dominant
mutations. unc-43 has a visible loss of-function phenotype,
and unc-ll0 has one, grossly wild-type putative loss-of-function
mutation. Therefore, they share the genetic characteristics
of the Mac genes. However, we observed that unc-43(n498sd)
appears Mac-h for body-wall muscle (suppressible by unc-54),
but Mac-d for egg-laying and enteric muscles. The unc-43
loss-of-function mutations appear Mac-d for body-wall
muscles, but are Mac-h for egg laying. Likewise, unc-ll0(el913sd)
animals are Mac-d for body-wall muscles, but are Mac-h
for egg laying. Therefore, these genes may positively
regulate some muscle tissues and negatively regulate
others. We have designated this phenotype Mac-m, for muscle
activation-mixed. We speculate that unc-43 and unc-ll0
are good candidates for regulatory signal transduction
pathway components. Further analysis of unc-43 is presented
in the gazette by Reiner and Thomas. this issue.
We'd like to thank and acknowledge the numerous workers
in the worm field that have isolated and analyzed mutations
in these loci, including (in alphabebical order): L. Avery,
I. Greenwald, B. Horvitz, E. Jorgensen, R. Lee, J. Levin,
E. Park, B. Schrank, D Thierry-Mieg, C. Trent, N. Tsung
and B. Waterston.