RESUMEN
A major barrier to regenerating axons after injury in the mammalian central nervous system is an unfavorable milieu. Three proteins found in myelin--Nogo, MAG, and OMgp--inhibit axon regeneration in vitro and bind to the glycosylphosphatidylinositol-anchored Nogo receptor (NgR). However, genetic deletion of NgR has only a modest disinhibitory effect, suggesting that other binding receptors for these molecules probably exist. With the use of expression cloning, we have found that paired immunoglobulin-like receptor B (PirB), which has been implicated in nervous system plasticity, is a high-affinity receptor for Nogo, MAG, and OMgp. Interfering with PirB activity, either with antibodies or genetically, partially rescues neurite inhibition by Nogo66, MAG, OMgp, and myelin in cultured neurons. Blocking both PirB and NgR activities leads to near-complete release from myelin inhibition. Our results implicate PirB in mediating regeneration block, identify PirB as a potential target for axon regeneration therapies, and provide an explanation for the similar enhancements of visual system plasticity in PirB and NgR knockout mice.
Asunto(s)
Axones/fisiología , Proteínas de la Mielina/metabolismo , Regeneración Nerviosa , Neuronas/citología , Neuronas/metabolismo , Receptores Inmunológicos/metabolismo , Secuencia de Aminoácidos , Animales , Células Cultivadas , Cerebelo/citología , Proteínas Ligadas a GPI , Ganglios Espinales/citología , Conos de Crecimiento/fisiología , Ratones , Datos de Secuencia Molecular , Glicoproteína Asociada a Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito , Neuritas/fisiología , Proteínas Nogo , Receptor Nogo 1 , Receptores de Superficie Celular/metabolismo , Receptores Inmunológicos/genética , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/metabolismoRESUMEN
Cancer is an age-related disease, and inhibiting insulin/insulin-like growth factor 1 (IGF-1) signaling extends lifespan and increases tumor resistance in C. elegans and mammals. To investigate how the insulin/IGF-1 pathway couples these two processes, we analyzed putative transcriptional targets of the C. elegans FOXO transcription factor DAF-16, which promotes both longevity and tumor resistance. Twenty-nine of 734 genes tested influenced germline-tumor cell proliferation or p53-dependent apoptosis. About half of these genes also affected normal aging, thereby linking these two processes mechanistically. Many of these 29 genes are orthologs of known human tumor suppressors or oncogenes, suggesting that others may be as well. Our findings implicate nuclear-pore modification in p53-dependent cell death, because inhibiting nuclear-pore genes that are upregulated by DAF-16 blocks p53-dependent cell death in the tumor, but not normal, p53-independent, germline cell death.
