RESUMEN
Ciliary neurotrophic factor (CNTF) administration maintains, protects, and promotes the regeneration of both motor neurons (MNs) and skeletal muscle in a wide variety of models. Expression of CNTF receptor α (CNTFRα), an essential CNTF receptor component, is greatly increased in skeletal muscle following neuromuscular insult. Together the data suggest that muscle CNTFRα may contribute to neuromuscular maintenance, protection, and/or regeneration in vivo. To directly address the role of muscle CNTFRα, we selectively-depleted it in vivo by using a "floxed" CNTFRα mouse line and a gene construct (mlc1f-Cre) that drives the expression of Cre specifically in skeletal muscle. The resulting mice were challenged with sciatic nerve crush. Counting of nerve axons and retrograde tracing of MNs indicated that muscle CNTFRα contributes to MN axonal regeneration across the lesion site. Walking track analysis indicated that muscle CNTFRα is also required for normal recovery of motor function. However, the same muscle CNTFRα depletion unexpectedly had no detected effect on the maintenance or regeneration of the muscle itself, even though exogenous CNTF has been shown to affect these functions. Similarly, MN survival and lesion-induced terminal sprouting were unaffected. Therefore, muscle CNTFRα is an interesting new example of a muscle growth factor receptor that, in vivo under physiological conditions, contributes much more to neuronal regeneration than to the maintenance or regeneration of the muscle itself. This novel form of muscle-neuron interaction also has implications in the therapeutic targeting of the neuromuscular system in MN disorders and following nerve injury. J. Comp. Neurol. 521: 2947-2965, 2013. © 2013 Wiley Periodicals, Inc.
Asunto(s)
Subunidad alfa del Receptor del Factor Neurotrófico Ciliar/uso terapéutico , Regeneración Nerviosa/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Neuropatía Ciática , Análisis de Varianza , Animales , Axones/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Peso Corporal/efectos de los fármacos , Peso Corporal/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Subunidad alfa del Receptor del Factor Neurotrófico Ciliar/genética , Modelos Animales de Enfermedad , Lateralidad Funcional , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Luminiscentes/metabolismo , Ratones , Ratones Transgénicos , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/genética , Fibras Musculares Esqueléticas/patología , Regeneración Nerviosa/genética , Unión Neuromuscular/efectos de los fármacos , Unión Neuromuscular/patología , ARN Mensajero , Receptores Colinérgicos/metabolismo , Recuperación de la Función/genética , Neuropatía Ciática/tratamiento farmacológico , Neuropatía Ciática/patología , Neuropatía Ciática/fisiopatología , Estilbamidinas , Caminata/fisiologíaRESUMEN
Appropriately targeted manipulation of endogenous neural stem progenitor (NSP) cells may contribute to therapies for trauma, stroke, and neurodegenerative disease. A prerequisite to such therapies is a better understanding of the mechanisms regulating adult NSP cells in vivo. Indirect data suggest that endogenous ciliary neurotrophic factor (CNTF) receptor signaling may inhibit neuronal differentiation of NSP cells. We challenged subventricular zone (SVZ) cells in vivo with low concentrations of CNTF to anatomically characterize cells containing functional CNTF receptors. We found that type B "stem" cells are highly responsive, whereas type C "transit-amplifying" cells and type A neuroblasts are remarkably unresponsive, as are GFAP(+) astrocytes found outside the SVZ. CNTF was identified in a subset of type B cells that label with acute BrdU administration. Disruption of in vivo CNTF receptor signaling in SVZ NSP cells, with a "floxed" CNTF receptor α (CNTFRα) mouse line and a gene construct driving Cre recombinase (Cre) expression in NSP cells, led to increases in SVZ-associated neuroblasts and new olfactory bulb neurons, as well as a neuron subtype-specific, adult-onset increase in olfactory bulb neuron populations. Adult-onset receptor disruption in SVZ NSP cells with a recombinant adeno-associated virus (AAV-Cre) also led to increased neurogenesis. However, the maintenance of type B cell populations was apparently unaffected by the receptor disruption. Together, the data suggest that endogenous CNTF receptor signaling in type B stem cells inhibits adult neurogenesis, and further suggest that the regulation may occur in a neuron subtype-specific manner.