Hypaxial skeletal muscles develop from migratory and non-migratory precursor cells that are generated by the lateral lip of the dermomyotome. Previous work shows that the formation of migratory precursors requires the c-Met and SF/HGF genes. We show here that in mice lacking c-Met or SF/HGF, the initial development of the dermomyotome proceeds appropriately and growth and survival of cells in the dermomyotome are not affected. Migratory precursors are also correctly specified, as monitored by the expression of Lbx1. However, these cells remain aggregated and fail to take up long range migration. We conclude that parallel but independent cues converge on the migratory hypaxial precursors in the dermomyotomal lip after they are laid down: a signal given by SF/HGF that controls the emigration of the precursors, and an as yet unidentified signal that controls Lbx1. SF/HGF and c-Met act in a paracrine manner to control emigration, and migratory cells only dissociate from somites located close to SF/HGF-expressing cells. During long range migration, prolonged receptor-ligand-interaction appears to be required, as SF/HGF is expressed both along the routes and at the target sites of migratory myogenic progenitors. Mice that lack c-Met die during the second part of gestation due to a placental defect. Rescue of the placental defect by aggregation of tetraploid (wild type) and diploid (c-Met−/−) morulae allows development of c-Met mutant animals to term. They lack muscle groups that derive from migratory precursor cells, but display otherwise normal skeletal musculature.

Reference

Anastasi
S.
,
Giordano
S.
,
Sthandier
O.
,
Gambarotta
G.
,
Maione
R.
,
Comoglio
P.
,
Amati
P.
(
1997
)
A natural hepatocyte growth factor/scatter factor autocrine loop in myoblast cells and the effect of the constitutive Met kinase activation on myogenic differentiation.
J. Cell Biol
137
,
1057
1068
Bladt
F.
,
Riethmacher
D.
,
Isenmann
S.
,
Aguzzi
A.
,
Birchmeier
C.
(
1995
)
Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud.
Nature
376
,
768
771
Bober
E.
,
Franz
T.
,
Arnold
H. H.
,
Gruss
P.
,
Tremblay
P.
(
1994
)
Pax-3 is required for the development of limb muscles: a possible role for the migration of dermomyotomal muscle progenitor cells.
Development
120
,
603
612
Bober
E.
,
Lyons
G. E.
,
Braun
T.
,
Cossu
G.
,
Buckingham
M.
,
Arnold
H. H.
(
1991
)
The muscle regulatory gene, Myf-6, has a biphasic pattern of expression during early mouse development.
J.Cell Biol
113
,
1255
1265
Brand-Saberi
B.
,
Muller
T. S.
,
Wilting
J.
,
Christ
B.
,
Birchmeier
C.
(
1996
)
Scatter factor hepatocyte growth factor (SF/HGF) induces emigration of myogenic cells at interlimb level in vivo.
Dev. Biol
179
,
303
308
Chevallier
A.
,
Kieny
M.
,
Mauger
A.
(
1977
)
Limb-somite relationship: origin of the limb musculature.
J. Embryol. Exp. Morphol
41
,
245
258
Christ
B.
,
Jacob
H. J.
,
Jacob
M.
(
1977
)
Experimental analysis of the origin of the wing musculature in avian embryos.
Anat. Embryol
150
,
171
186
Christ
B.
,
Jacob
M.
,
Jacob
H. J.
(
1983
)
On the origin and development of the ventrolateral abdominal muscles in the avian embryo. An experimental and ultrastructural study.
Anat. Embryol
166
,
87
101
Christ
B.
,
Ordahl
C. P.
(
1995
)
Early stages of chick somite development.
Anat. Embryol
191
,
381
396
Cornelison
D. D.
,
Wold
B. J.
(
1997
)
Single-cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells.
Dev. Biol
191
,
270
283
Cossu
G.
,
Tajbakhsh
S.
,
Buckingham
M.
(
1996
)
How is myogenesis initiated in the embryo?.
Trends Genet
12
,
218
223
Daston
G.
,
Lamar
E.
,
Olivier
M.
,
Goulding
M.
(
1996
)
Pax3 is necessary for migration but not differentiation of limb muscle precursors in the mouse.
Development
122
,
1017
1027
Denetclaw
W. J.
,
Christ
B.
,
Ordahl
C. P.
(
1997
)
Location and growth of epaxial myotome precursor cells.
Development
124
,
1601
1610
Dietrich
S.
,
Schubert
F. R.
,
Healy
C.
,
Sharpe
P. T.
,
Lumsden
A.
(
1998
)
Specification of the hypaxial musculature.
Development
125
,
2235
2249
Epstein
J. A.
,
Shapiro
D. N.
,
Cheng
J.
,
Lam
P. Y.
,
Maas
R. L.
(
1996
)
Pax3 modulates expression of the c-Met receptor during limb muscle development.
Proc. Natl. Acad. Sci. USA
93
,
4213
4218
Fan
C. M.
,
Kuwana
E.
,
Bulfone
A.
,
Fletcher
C. F.
,
Copeland
N. G.
,
Jenkins
N. A.
,
Crews
S.
,
Martinez
S.
,
Puelles
L.
,
Rubenstein
J. L.
,
Tessier-Lavigne
M.
(
1996
)
Expression patterns of two murine homologs of Drosophila single-minded suggest possible roles in embryonic patterning and in the pathogenesis of Down syndrome.
Mol. Cell Neurosci
7
,
1
16
Franz
T.
,
Kothary
R.
,
Surani
M. A.
,
Halata
Z.
,
Grim
M.
(
1993
)
The Splotch mutation interferes with muscle development in the limbs.
Anat. Embryol
187
,
153
160
Gal
L. R.
,
Leshem
Y.
,
Aoki
S.
,
Nakamura
T.
,
Halevy
O.
(
1998
)
Hepatocyte growth factor plays a dual role in regulating skeletal muscle satellite cell proliferation and differentiation.
Biochim. Biophys. Acta
1402
,
39
51
Goulding
M.
,
Lumsden
A.
,
Paquette
A. J.
(
1994
)
Regulation of Pax-3 expression in the dermomyotome and its role in muscle development.
Development
120
,
957
971
Goulding
M. D.
,
Chalepakis
G.
,
Deutsch
U.
,
Erselius
J. R.
,
Gruss
P.
(
1991
)
Pax-3, a novel murine DNA binding protein expressed during early neurogenesis.
EMBO J
10
,
1135
1147
Heymann
S.
,
Koudrova
M.
,
Arnold
H. H.
,
Koster
M.
,
Braun
T.
(
1996
)
Regulation and function of SF/HGF during migration of limb muscle precursor cells in chicken.
Dev. Biol
180
,
566
578
Jacob
M.
,
Christ
B.
,
Jacob
H. J.
(
1978
)
On the migration of myogenic stem cells into the prospective wing region of chick embryos. A scanning and transmission electron microscope study.
Anat. Embryol
153
,
179
193
Jacob
M.
,
Christ
B.
,
Jacob
H. J.
(
1979
)
The migration of myogenic cells from the somites into the leg region of avian embryos. An ultrastructural study.
Anat. Embryol
157
,
291
309
Jagla
K.
,
Dolle
P.
,
Mattei
M. G.
,
Jagla
T.
,
Schuhbaur
B.
,
Dretzen
G.
,
Bellard
F.
,
Bellard
M.
(
1995
)
Mouse Lbx1 and human LBX1 define a novel mammalian homeobox gene family related to the Drosophila lady bird genes.
Mech. Dev
53
,
345
356
James
R. M.
,
Klerkx
A.
,
Keighren
M.
,
Flockhart
J. H.
,
West
J. D.
(
1995
)
Restricted distribution of tetraploid cells in mouse tetraploid-diploid chimeras.
Dev. Biol
167
,
213
226
Jostes
B.
,
Walther
C.
,
Gruss
P.
(
1990
)
The murine paired box gene, Pax7, is expressed specifically during the development of the nervous and muscular system.
Mech. Dev
33
,
27
37
Maina
F.
,
Casagranda
F.
,
Audero
E.
,
Simeone
A.
,
Comoglio
P. M.
,
Klein
R.
,
Ponzetto
C.
(
1996
)
Uncoupling of Grb2 from the met receptor in vivo reveals complex roles in muscle development.
Cell
87
,
531
542
Mennerich
D.
,
Schäfer
K.
,
Braun
T.
(
1998
)
Pax-3 is necessary but not sufficient for lbx1 expression in myogenic precursor cells.
Mech. Dev
73
,
147
158
Noden
D. M.
(
1983
)
The embryonic origins of avian cephalic and cervical muscles and associated connective tissues.
Am. J. Anat
168
,
257
276
Ohuchi
H.
,
Nakagawa
T.
,
Yamamoto
A.
,
Araga
A.
,
Ohata
T.
,
Ishimaru
Y.
,
Yoshioka
H.
,
Kuwana
T.
,
Nohno
T.
,
Yamasaki
M.
,
Itoh
N.
,
Noji
S.
(
1997
)
The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor.
Development
124
,
2235
2244
Ordahl
C. P.
,
Le Douarin
N. M.
(
1992
)
Two myogenic lineages within the developing somite.
Development
114
,
339
53
Pourquie
O.
,
Fan
C. M.
,
Coltey
M.
,
Hirsinger
E.
,
Watanabe
Y.
,
Breant
C.
,
Francis-West
P.
,
Brickell
P.
,
Tessier-Lavigne
M.
,
Le Douarin
N. M.
(
1996
)
Lateral and axial signals involved in avian somite patterning: a role for BMP4.
Cell
84
,
461
471
Pownall
M. E.
,
Emerson
C. J.
(
1992
)
Sequential activation of three myogenic regulatory genes during somite morphogenesis in quail embryos.
Dev. Biol
151
,
67
79
Schemainda
H.
(
1979
)
Über die Entwicklung der occipitalen Somiten. Experimentelle Untersuchungen an Wachtel-und Huhnerembryonen.
Verh. Anat. Ges
73
,
527
532
Schmidt
C.
,
Bladt
F.
,
Goedecke
S.
,
Brinkmann
V.
,
Zschiesche
W.
,
Sharpe
M.
,
Gherardi
E.
,
Birchmeier
C.
(
1995
)
Scatter factor/hepatocyte growth factor is essential for liver development.
Nature
373
,
699
702
Smith
T. H.
,
Kachinsky
A. M.
,
Miller
J. B.
(
1994
)
Somite subdomains, muscle cell origins, and the four muscle regulatory factor proteins.
J. Cell Biol
127
,
95
105
Sonnenberg
E.
,
Meyer
D.
,
Weidner
K. M.
,
Birchmeier
C.
(
1993
)
Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development.
J. Cell Biol
123
,
223
235
Tajbakhsh
S.
,
Rocancourt
D.
,
Cossu
G.
,
Buckingham
M.
(
1997
)
Redefining the genetic hierarchies controlling skeletal myogenesis: Pax3 and Myf5 act upstream of MyoD.
Cell
89
,
127
138
Tatsumi
R.
,
Anderson
J. E.
,
Nevoret
C. J.
,
Halevy
O.
,
Allen
R. E.
(
1998
)
HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells.
Dev. Biol
194
,
114
128
Thery
C.
,
Sharpe
M. J.
,
Batley
S. J.
,
Stern
C. D.
,
Gherardi
E.
(
1995
)
Expression of HGF/SF, HGF1/MSP, and c-met suggests new functions during early chick development.
Dev. Genet
17
,
90
101
Tremblay
P.
,
Dietrich
S.
,
Schubert
F. R.
,
Meriskay
M.
,
Paulin
D.
(
1998
)
A crucial role for Pax3 in the development of the hypaxial musculature and the long-range migration of muscle precursors.
Dev. Biol
203
,
49
61
Uehara
Y.
,
Minowa
O.
,
Mori
C.
,
Shiota
K.
,
Kuno
J.
,
Noda
T.
,
Kitamura
N.
(
1995
)
Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor.
Nature
373
,
702
705
Webb
S. E.
,
Lee
K. K. H.
,
Tang
M. K.
,
Ede
D. A.
(
1997
)
Fibroblast Growth Factors 2 and 4 stimulate migration of mouse embryonic limb myogenic cells.
Dev. Dynam
209
,
206
216
Williams
B. A.
,
Ordahl
C. P.
(
1994
)
Pax-3 expression in segmental mesoderm marks early stages in myogenic cell specification.
Development
120
,
785
796
Yang
X. M.
,
Vogan
K.
,
Gros
P.
,
Park
M.
(
1996
)
Expression of the met receptor tyrosine kinase in muscle progenitor cells in somites and limbs is absent in Splotch mice.
Development
122
,
2163
2171
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