RESUMEN
Mice lacking a functional NGF gene (ngf-/- mice) have less than one third of the normal complement of sensory neurons, few sympathetic postganglionic neurons and die shortly after birth. We report here that transgenic expression of NGF under control of the K14 keratin promoter can rescue some elements of the peripheral nervous system and restore normal growth and viability to ngf-/- mice. While hybrid transgenic-ngf-/- mice (ngfTKOs) displayed marginal rescue of trigeminal ganglion neurons, the percentage of CGRP-positive neurons was restored to normal. Restoration of CGRP-positive terminals in skin and spinal cord was also found and accompanied by recovery of behavioral responses to noxious stimuli. ngfTKO mice displayed a normal number of superior cervical ganglion neurons and recovery of sympathetic innervation of skin. These results demonstrate that substitution of a functional NGF locus by a transgene directing expression largely to skin can result in normal growth and viability. Thus, the most vital functions of NGF are not dependent on faithful recapitulation of the normal spatiotemporal pattern of gene expression.
Asunto(s)
Factor de Crecimiento Nervioso/deficiencia , Neuronas Aferentes/metabolismo , Sistema Nervioso Periférico/anomalías , Anomalías Cutáneas/genética , Piel/crecimiento & desarrollo , Fibras Simpáticas Posganglionares/anomalías , Animales , Supervivencia Celular/genética , Femenino , Ganglios Simpáticos/anomalías , Ganglios Simpáticos/citología , Ganglios Simpáticos/crecimiento & desarrollo , Regulación del Desarrollo de la Expresión Génica/genética , Terapia Genética/métodos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Factor de Crecimiento Nervioso/biosíntesis , Factor de Crecimiento Nervioso/genética , Neuronas Aferentes/citología , Nociceptores/anomalías , Nociceptores/citología , Nociceptores/crecimiento & desarrollo , Dolor/genética , Dolor/metabolismo , Sistema Nervioso Periférico/citología , Sistema Nervioso Periférico/crecimiento & desarrollo , Células Receptoras Sensoriales/anomalías , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/crecimiento & desarrollo , Piel/inervación , Piel/metabolismo , Anomalías Cutáneas/metabolismo , Fibras Simpáticas Posganglionares/citología , Fibras Simpáticas Posganglionares/crecimiento & desarrollo , Transgenes/genética , Ganglio del Trigémino/anomalías , Ganglio del Trigémino/citología , Ganglio del Trigémino/crecimiento & desarrolloRESUMEN
Association and relay neurons that are generated in the dorsal spinal cord play essential roles in transducing somatosensory information. During development, these two major neuronal classes are delineated by the expression of the homeodomain transcription factor Lbx1. Lbx1 is expressed in and required for the correct specification of three early dorsal interneuron populations and late-born neurons that form the substantia gelatinosa. In mice lacking Lbx1, cells types that arise in the ventral alar plate acquire more dorsal identities. This results in the loss of dorsal horn association interneurons, excess production of commissural neurons, and disrupted sensory afferent innervation of the dorsal horn. Lbx1, therefore, plays a critical role in the development of sensory pathways in the spinal cord that relay pain and touch.
Asunto(s)
Tipificación del Cuerpo/genética , Diferenciación Celular/genética , Linaje de la Célula/genética , Regulación del Desarrollo de la Expresión Génica/genética , Interneuronas/metabolismo , Proteínas Musculares/genética , Células del Asta Posterior/anomalías , Vías Aferentes/anomalías , Vías Aferentes/citología , Vías Aferentes/metabolismo , Animales , Apoptosis/genética , Axones/metabolismo , Axones/ultraestructura , Movimiento Celular/genética , Femenino , Interneuronas/citología , Masculino , Ratones , Ratones Transgénicos , Proteínas Musculares/metabolismo , Mutación/genética , Fibras Nerviosas/metabolismo , Fibras Nerviosas/ultraestructura , Fibras Nerviosas Mielínicas/metabolismo , Fibras Nerviosas Mielínicas/ultraestructura , Vías Nerviosas/anomalías , Vías Nerviosas/citología , Vías Nerviosas/metabolismo , Nociceptores/anomalías , Nociceptores/citología , Nociceptores/metabolismo , Células del Asta Posterior/citología , Células del Asta Posterior/metabolismo , Receptor trkA/genética , Receptor trkA/metabolismo , Sustancia Gelatinosa/anomalías , Sustancia Gelatinosa/citología , Sustancia Gelatinosa/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
To investigate the nerve growth factor requirement of developing oro-facial somatosensory afferents, we have studied the survival of sensory fibers subserving nociception, mechanoreception or proprioception in receptor tyrosine kinase (trkA) knockout mice using immunohistochemistry. trkA receptor null mutant mice lack nerve fibers in tooth pulp, including sympathetic fibers, and showed only sparse innervation of the periodontal ligament. Ruffini endings were formed definitively in the periodontal ligament of the trkA knockout mice, although calcitonin gene-related peptide- and substance P-immunoreactive fibers were reduced in number or had disappeared completely. trkA gene deletion had also no obvious effect on the formation of Meissner corpuscles in the palate. In the vibrissal follicle, however, some mechanoreceptive afferents were sensitive for trkA gene deletion, confirming a previous report [Fundin et al. (1997) Dev. Biol. 190, 94-116]. Moreover, calretinin-positive fibers innervating longitudinal lanceolate endings were completely lost in trkA knockout mice, as were the calretinin-containing parent cells in the trigeminal ganglion.These results indicate that trkA is indispensable for developing nociceptive neurons innervating oral tissues, but not for developing mechanoreceptive neurons innervating oral tissues (Ruffini endings and Meissner corpuscles), and that calretinin-containing, trkA dependent neurons in the trigeminal ganglion normally participate in mechanoreception through longitudinal lanceolate endings of the vibrissal follicle.
