CXCR4 and Gab1 cooperate to control the development of migrating muscle progenitor cells.
Long-range migrating progenitor cells generate hypaxial muscle, for instance the muscle of the limbs, hypoglossal cord, and diaphragm. We show here that migrating muscle progenitors express the chemokine receptor CXCR4. The corresponding ligand, SDF1, is expressed in limb and branchial arch mesenchyme; i.e., along the routes and at the targets of the migratory cells. Ectopic application of SDF1 in the chick limb attracts muscle progenitor cells. In CXCR4 mutant mice, the number of muscle progenitors that colonize the anlage of the tongue and the dorsal limb was reduced. Changes in the distribution of the muscle progenitor cells were accompanied by increased apoptosis, indicating that CXCR4 signals provide not only attractive cues but also control survival. Gab1 encodes an adaptor protein that transduces signals elicited by tyrosine kinase receptors, for instance the c-Met receptor, and plays a role in the migration of muscle progenitor cells. We found that CXCR4 and Gab1 interact genetically. For instance, muscle progenitors do not reach the anlage of the tongue in CXCR4;Gab1 double mutants; this target is colonized in either of the single mutants. Our analysis reveals a role of SDF1/CXCR4 signaling in the development of migrating muscle progenitors and shows that a threshold number of progenitor cells is required to generate muscle of appropriate size.
Vasyutina
Elena
E
Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany.
Stebler
Jürg
J
Brand-Saberi
Beate
B
Schulz
Stefan
S
Raz
Erez
E
Birchmeier
Carmen
C
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D018929:Cell Culture Techniques; D002465:Cell Movement; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D002642:Chick Embryo; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D047108:Embryonic Development; D016368:Frameshift Mutation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000196:embryology*; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C490897:Gab1 protein, mouse; D010750:Phosphoproteins; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins