Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis.
The chemokine CXCL12/SDF-1 and its receptor CXCR4 regulate the development and the function of the hematopoietic system and control morphogenesis of distinct brain areas. Here, we demonstrate that inactivation of CXCR4 results in a massive loss of spinal cord motoneurons and dorsal root ganglion neurons and, subsequently, in a reduced innervation of the developing mouse fore- and hindlimbs. However, only the death of sensory neurons seems to be a direct consequence of receptor inactivation as suggested by the observations that DRG neurons, but not motoneurons, of wild-type animals express CXCR4 and respond to CXCL12 with an increase in cell survival. In contrast, the increased death of motoneurons in CXCR4-deficient animals seems to result from impaired limb myogenesis and a subsequent loss of muscle-derived neurotrophic support. In summary, our findings unravel a previously unrecognized complex role of CXCL12/CXCR4 in the control of limb neuromuscular development.
Odemis
Veysel
V
Institute of Anatomy, University of Leipzig, Medical Faculty, Liebigstr. 13, 04103 Leipzig, Germany.
Lamp
Elke
E
Pezeshki
Gita
G
Moepps
Barbara
B
Schilling
Karl
K
Gierschik
Peter
P
Littman
Dan R
DR
Engele
Jürgen
J
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism / Q000494:pharmacology; D005121:Extremities; D005260:Female; D005727:Ganglia, Spinal / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D017880:Limb Deformities, Congenital / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000002:abnormalities* / Q000294:innervation* / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000172:deficiency; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010525:Peripheral Nerves / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology; D019718:Receptors, CXCR4 / Q000235:genetics*; D013116:Spinal Cord / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D009414:Nerve Growth Factors; D019718:Receptors, CXCR4