Toba Yoko, Tiong Jean D, Ma Qing, Wray Susan
Cellular and Developmental Neurobiology Section, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
Dev Neurobiol. 2008 Mar;68(4):487-503. doi: 10.1002/dneu.20594.
Stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 influence neuronal migration and have been identified in nasal regions. Gonadotropin releasing hormone-1 (GnRH-1) neurons migrate from nasal regions into the developing forebrain, where postnatally they control reproduction. This study examined the role of SDF-1/CXCR4 in development of the GnRH-1/olfactory systems. Migrating GnRH-1 neurons were CXCR4 immunopositive as were the fibers along which they migrate. SDF-1 transcripts were detected in olfactory epithelium and vomeronasal organ, while SDF-1 immunoreactivity highlighted the GnRH-1 migratory pathway. CXCR4-deficient mice showed a decrease in GnRH-1 cells at the nasal forebrain junction and in brain, but the overall migratory pathway remained intact, no ectopic GnRH-1 cells were detected and olfactory axons reached the olfactory bulb. To further characterize the influence of SDF-1/CXCR4 in the GnRH-1 system, nasal explants were used. CXCR4 expression in vitro was similar to that in vivo. SDF-1 was detected in a dorsal midline cell cluster as well as in migrating GnRH-1 cells. Treatment of explants with bicyclam AMD3100, a CXCR4 antagonist, attenuated GnRH-1 neuronal migration and sensory axon outgrowth. Moreover, the number of GnRH-1 neurons in the explant periphery was reduced. The effects were blocked by coincubation with SDF-1. Removal of midline SDF-1 cells did not alter directional outgrowth of olfactory axons. These results indicate that SDF-1/CXCR4 signaling in not necessary for olfactory axon guidance but rather influences sensory axon extension and GnRH-1 neuronal migration, and maintains GnRH-1 neuronal expression as the cells move away from nasal pit regions.
基质细胞衍生因子1(SDF-1)及其受体CXCR4影响神经元迁移,并且已在鼻腔区域被发现。促性腺激素释放激素-1(GnRH-1)神经元从鼻腔区域迁移至发育中的前脑,出生后它们在此处控制生殖。本研究检测了SDF-1/CXCR4在GnRH-1/嗅觉系统发育中的作用。迁移的GnRH-1神经元及其迁移所沿的纤维均为CXCR4免疫阳性。在嗅觉上皮和犁鼻器中检测到SDF-1转录本,而SDF-1免疫反应性突出了GnRH-1的迁移途径。CXCR4缺陷小鼠在鼻前脑交界处和脑中的GnRH-1细胞减少,但整体迁移途径保持完整,未检测到异位GnRH-1细胞,且嗅觉轴突到达嗅球。为进一步阐明SDF-1/CXCR4对GnRH-1系统的影响,使用了鼻外植体。体外CXCR4表达与体内相似。在背中线细胞簇以及迁移的GnRH-1细胞中检测到SDF-1。用CXCR4拮抗剂双环胺AMD3100处理外植体,可减弱GnRH-1神经元迁移和感觉轴突生长。此外,外植体周边的GnRH-1神经元数量减少。这些作用可被与SDF-1共同孵育所阻断。去除中线SDF-1细胞并未改变嗅觉轴突的定向生长。这些结果表明,SDF-1/CXCR4信号传导对于嗅觉轴突导向并非必需,而是影响感觉轴突延伸和GnRH-1神经元迁移,并在细胞从鼻凹区域移开时维持GnRH-1神经元表达。