Harrison Susan M W, Davis Brian M, Nishimura Merry, Albers Kathryn M, Jones Marc E, Phillips Heidi S
School of Biological Sciences, University of Kentucky, Lexington, KY 40506, USA.
Brain Res Mol Brain Res. 2004 Mar 30;122(2):116-25. doi: 10.1016/j.molbrainres.2003.12.004.
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.
缺乏功能性NGF基因的小鼠(ngf-/-小鼠)的感觉神经元数量不到正常数量的三分之一,交感神经节后神经元数量很少,且在出生后不久就死亡。我们在此报告,在K14角蛋白启动子控制下的NGF转基因表达可以挽救外周神经系统的一些成分,并使ngf-/-小鼠恢复正常生长和生存能力。虽然杂交转基因-ngf-/-小鼠(ngfTKO)对三叉神经节神经元的挽救作用微弱,但CGRP阳性神经元的百分比恢复到了正常水平。还发现皮肤和脊髓中CGRP阳性终末得到恢复,并伴随着对有害刺激的行为反应的恢复。ngfTKO小鼠的颈上神经节神经元数量正常,皮肤的交感神经支配也得到恢复。这些结果表明,通过主要定向表达于皮肤的转基因替代功能性NGF基因座可导致正常生长和生存能力。因此,NGF的最重要功能并不依赖于对基因表达正常时空模式的忠实重现。