Sex myoblast migration in the Caenorhabditis elegans hermaphrodite represents a simple, genetically amenable model system for studying how cell migration is regulated during development. Two separable components of sex myoblast guidance have been described: a gonad-independent mechanism sufficient for the initial anterior migration to the mid-body region, and a gonad-dependent mechanism required for precise final positioning (J. H. Thomas, M. J. Stern and H. R. Horvitz (1990) Cell 62, 1041–1052). Here, we demonstrate a role for a Ras-mediated signal transduction pathway in controlling sex myoblast migration. Loss-of-function mutations in let-60 ras, ksr-1, lin-45 raf, let-537/mek-2 or sur-1/mpk-1 cause defects in sex myoblast final positions that resemble those seen in gonad-ablated animals, while constitutively active let-60 ras(G13E) trans-genes allow fairly precise positioning to occur in the absence of the gonad. A mosaic analysis demonstrated that let-60 ras is required within the sex myoblasts to control proper positioning. Our results suggest that gonadal signals normally stimulate let-60 ras activity in the sex myoblasts, thereby making them competent to sense or respond to positional cues that determine the precise endpoint of migration. let-60 ras may have additional roles in sex myoblast guidance as well. Finally, we have also investigated genetic interactions between let-60 ras and other genes important for sex myoblast migration, including egl-15, which encodes a fibroblast growth factor receptor tyrosine kinase (D. L. DeVore, H. R. Horvitz and M. J. Stern (1995) Cell 83, 611–623). Since mutations reducing Ras pathway activity cause a different phenotype than those reducing egl-15 activity and since constitutive Ras activity only partially suppresses the migration defects of egl-15 mutants, we argue that let-60 ras and egl-15 do not act together in a single linear pathway.

Reference

Reference
Aroian
R. V.
,
Koga
M.
,
Mendel
J. E.
,
Ohshima
Y.
,
Sternberg
P. W.
(
1990
)
The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily.
Nature
348
,
693
699
Aroian
R. V.
,
Sternberg
P. W.
(
1991
)
Multiple functions of let-23, a Caenorhabditis elegans receptor tyrosine kinase gene required for vulval induction.
Genetics
128
,
251
267
Avery
L.
,
Horvitz
H. R.
(
1987
).
A cell that dies during wild-type C. elegans development can function as a neuron in a ced-3 mutant.
Cell
51
,
1071
1078
Beitel
G. J.
,
Clark
S. G.
,
Horvitz
H. R.
(
1990
)
Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction.
Nature
348
,
503
509
Beitel
G. J.
,
Tuck
S.
,
Greenwald
I.
,
Horvitz
H. R.
(
1995
)
The C. elegans gene lin-1 encodes an ETS-domain protein and defines a branch of the vulval induction pathway.
Genes Dev
9
,
3149
3162
Bos
J. L.
,
Toksoz
D.
,
Marshall
C. J.
,
Verlaan-de Vries
M.
,
Veeneman
G. H.
,
van der Eb
A. J.
,
van Boom
J. H.
,
Janssen
J. W. G.
,
Steenvoorden
A. C. M.
(
1985
)
Amino acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia.
Nature
315
,
726
730
Clark
D. V.
,
Rogalski
T. M.
,
Donati
L. M.
,
Baillie
D. L.
(
1988
)
The unc-22(IV) region of Caenorhabditis elegans: genetic analysis of lethal mutations.
Genetics
119
,
345
353
Clark
S. G.
,
Lu
X.
,
Horvitz
H. R.
(
1994
)
The Caenorhabditis elegans locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins.
Genetics
137
,
987
997
Clark
S. G.
,
Stern
M. J.
,
Horvitz
H. R.
(
1992
)
C. elegans cell-signaling gene sem-5 encodes a protein with SH2 and SH3 domains.
Nature
356
,
340
344
Clark
S. G.
,
Stern
M. J.
,
Horvitz
H. R.
(
1992
)
Genes involved in two Caenorhabditis elegans cell-signaling pathways.
Cold Spring Harbor Symp. Quant. Biol
57
,
363
373
DeVore
D. L.
,
Horvitz
H. R.
,
Stern
M. J.
(
1995
)
An FGF Receptor signaling pathway is required for the normal migrations of the sex myoblasts in C. elegans hermaphrodites.
Cell
83
,
611
620
Glazer
L.
,
Shilo
B.
(
1991
)
The Drosophila FGF-R homolog is expressed in the embryonic tracheal system and appears to be required for directed tracheal cell extension.
Genes Dev
5
,
697
705
Greenwald
I. S.
,
Sternberg
P. W.
,
Horvitz
H. R.
(
1983
)
The lin-12 locus specifies cell fates in Caenorhabditis elegans.
Cell
34
,
435
444
Han
M.
,
Sternberg
P. W.
(
1990
)
let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a Ras protein.
Cell
63
,
921
931
Han
M.
,
Sternberg
P. W.
(
1991
)
Analysis of dominant-negative mutations of the Caenorhabditis elegans let-60 ras gene.
Genes Dev
5
,
2188
2198
Han
M.
,
Aroian
R. V.
,
Sternberg
P. W.
(
1990
)
The let-60 locus controls the switch between vulval and nonvulval cell fates in Caenorhabditis elegans.
Genetics
126
,
899
913
Han
M.
,
Golden
A.
,
Han
Y.
,
Sternberg
P. W.
(
1993
)
C. elegans lin-45 raf gene participates in let-60 ras -stimulated vulval differentiation.
Nature
363
,
133
140
Hedgecock
E. M.
,
Herman
R. K.
(
1995
)
The ncl-1 gene and genetic mosaics of Caenorhabditis elegans.
Genetics
141
,
989
1006
Herman
M. A.
,
Vassilieva
L. L.
,
Horvitz
H. R.
,
Shaw
J. E.
,
Herman
R. K.
(
1995
)
The C. elegans gene lin-44, which controls the polarity of certain asymmetric cell divisions, encodes a Wnt protein and acts cell nonautonomously.
Cell
83
,
101
110
Hodgkin
J.
,
Horvitz
H. R.
,
Brenner
S.
(
1979
)
Nondisjunction mutants of the nematode Caenorhabditis elegans.
Genetics
91
,
67
94
Huang
L.
,
Tzou
P.
,
Sternberg
P. W.
(
1994
)
The lin-15 locus encodes two negative regulators of Caenorhabditis elegans vulval development.
Mol. Biol. Cell
5
,
395
411
Kayne
P. S.
,
Sternberg
P. W.
(
1995
)
Ras pathways in Caenorhabditis elegans.
Curr. Opin. Gen. Dev
5
,
1
–.
Klambt
C.
,
Glazer
L.
,
Shilo
B.
(
1992
)
breathless, a Drosophila FGF Receptor homolog, is essential for migration of tracheal and specific midline glial cells.
Genes Dev
6
,
1668
1678
Kornfeld
K.
,
Guan
K. L.
,
Horvitz
H. R.
(
1995
)
The Caenorhabditis elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK.
Genes Dev
9
,
756
768
Kornfeld
K.
,
Hom
D. B.
,
Horvitz
H. R.
(
1995
)
The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans.
Cell
83
,
903
913
Lee
T.
,
Feig
L.
,
Montell
D.
(
1996
)
Two distinct roles for Ras in a developmentally regulated cell migration.
Development
122
,
409
418
MacNicol
A. M.
,
Muslin
A. J.
,
Williams
L. T.
(
1993
)
Raf-1 kinase is essential for early Xenopus development and mediates the induction of mesoderm by FGF.
Cell
73
,
571
583
Miller
L. M.
,
Gallegos
M. E.
,
Morisseau
B. A.
,
Kim
S. K.
(
1993
)
lin-31, a Caenorhabditis elegans HNF-3/forkhead transcription factor homolog, specifies three alternative cell fates in vulval development.
Genes Dev
7
,
933
947
Moerman
D.
,
Baillie
D.
(
1979
)
Genetic organization in Caenorhabditis elegans: fine structure analysis of the unc-22 gene.
Genetics
91
,
95
103
Reichman-Fried
M.
,
Dickson
B.
,
Hafen
E.
,
Shilo
B.
(
1994
)
Elucidation of the role of breathless, a Drosophila FGF receptor homolog, in tracheal cell migration.
Genes Dev
8
,
428
439
Sosnowski
R. G.
,
Feldman
S.
,
Feramisco
J. R.
(
1993
)
Interference with enodgenous Ras function inhibits cellular responses to wounding.
J. Cell Biol
121
,
113
119
Stern
M. J.
,
Horvitz
H. R.
(
1991
)
A normally attractive cell interaction is repulsive in two C. elegans mesodermal cell migration mutants.
Development
113
,
797
803
Sundaram
M.
,
Han
M.
(
1995
)
The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in ras-mediated signal transduction.
Cell
83
,
889
901
Sundaram
M.
,
Han
M.
(
1996
)
Control and integration of cell signaling pathways during C. elegans vulval development.
BioEssays
18
,
473
480
Thomas
J. H.
,
Stern
M. J.
,
Horvitz
H. R.
(
1990
)
Cell interactions coordinate the development of the C. elegans egg-laying system.
Cell
62
,
1041
1052
Umbhauer
M.
,
Marshall
C. J.
,
Mason
C. S.
,
Old
R. W.
,
Smith
J. C.
(
1995
)
Mesoderm induction in Xenopus caused by activation of MAP kinase.
Nature
376
,
58
62
Whitman
M.
,
Melton
D.
(
1992
)
Involvement of p21 ras in Xenopus mesoderm induction.
Nature
357
,
252
255
Wood
K. W.
,
Sarnecki
C.
,
Roberts
T.
,
Blenis
J.
(
1992
)
Ras mediates nerve growth factor receptor modulation of three signal transducing proteins: MAP kinase, Raf-1, and RSK.
Cell
68
,
1041
1050
Wu
Y.
,
Han
M.
(
1994
)
Suppression of activated Let-60 Ras protein defines a role of Caenorhabditis elegans Sur-1/mpk-1 MAP kinase in vulval differentiation.
Genes Dev
8
,
147
159
Wu
Y.
,
Han
M.
,
Guan
K. L.
(
1995
)
MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events.
Genes Dev
9
,
742
755
This content is only available via PDF.