Luukko K, Suvanto P, Saarma M, Thesleff I
Program of Developmental Biology, Institute of Biotechnology, University of Helsinki, Finland.
Dev Dyn. 1997 Dec;210(4):463-71. doi: 10.1002/(SICI)1097-0177(199712)210:4<463::AID-AJA9>3.0.CO;2-E.
Glial cell line-derived neurotrophic factor (GDNF) is a recently identified survival factor for several populations of neurons in the central and peripheral nervous system that also regulates kidney development. To study the roles of GDNF in the regulation of tooth innervation and formation, we analyzed by in situ hybridization the expression patterns of GDNF and its receptors Ret, GDNF family receptor alpha-1 (GFRalpha-1), and GFRalpha-2 from the initiation of first molar formation to the completion of crown morphogenesis. At the time of trigeminal axon ingrowth, GDNF mRNAs were expressed in the mesenchyme around the tooth germ (i.e., target field of the dental innervation), suggesting that it is involved in the regulation of the embryonic tooth innervation. This hypothesis was supported by the ability of GDNF to induce neurite outgrowth from embryonic day 12 (E12) to E15 trigeminal ganglia. This timing correlated with the appearance of Ret in the subset of cells in the trigeminal ganglion at E12, whereas GFRalpha-1 and GFRalpha-2 receptors were constantly expressed in trigeminal ganglion during E11-E15. After birth, GDNF expression showed apparent correlation with the ingrowth and presence of trigeminal nerve fibers in the tooth, suggesting that GDNF is involved in the regulation of innervation of the dental papilla and dentin postnatally. Ret, GFRalpha-1, and GFRalpha-2 mRNAs were expressed in the dental epithelial and mesenchymal cells at stages when epithelial-mesenchymal signalling regulates critical steps of tooth morphogenesis. Ret and GFRalpha-2 were colocalized in the dental mesenchyme during bud and cap stages. Expression of GFRalpha-1 associated with the formation of the epithelial enamel knot, which is a putative embryonic signalling center regulating tooth shape. During postnatal development, GDNF and its receptors were expressed in dental papilla mesenchyme. In addition, GDNF and GFRalpha-1 transcripts were seen in the preodontoblasts and odontoblasts, suggesting that they may be involved in differentiation and maintenance of functional properties of the odontoblasts. Taken together, these results suggest that GDNF acts as a target-derived neurotrophic factor during tooth innervation. In addition, GDNF and its receptors may have nonneuronal organogenetic functions during tooth morphogenesis.
胶质细胞源性神经营养因子（GDNF）是最近发现的一种对中枢和外周神经系统中几类神经元具有存活作用的因子，它还能调节肾脏发育。为了研究GDNF在牙齿神经支配和形成调节中的作用，我们通过原位杂交分析了从第一磨牙开始形成到牙冠形态发生完成过程中GDNF及其受体Ret、GDNF家族受体α-1（GFRα-1）和GFRα-2的表达模式。在三叉神经轴突长入时，GDNF mRNA在牙胚周围的间充质中表达（即牙齿神经支配的靶区域），这表明它参与胚胎期牙齿神经支配的调节。GDNF能够诱导胚胎第12天（E12）至E15三叉神经节的神经突生长，这一结果支持了上述假说。这个时间点与E12时三叉神经节中一部分细胞中Ret的出现相关，而GFRα-1和GFRα-2受体在E11 - E15期间在三叉神经节中持续表达。出生后，GDNF的表达与三叉神经纤维在牙齿中的长入和存在明显相关，这表明GDNF在出生后参与牙乳头和牙本质神经支配的调节。在上皮 - 间充质信号调节牙齿形态发生关键步骤的阶段，Ret、GFRα-1和GFRα-2 mRNA在牙上皮和间充质细胞中表达。在蕾状期和帽状期，Ret和GFRα-2在牙间充质中共定位。GFRα-1的表达与上皮釉结的形成相关，上皮釉结是一个假定的调节牙齿形状的胚胎信号中心。在出生后发育过程中，GDNF及其受体在牙乳头间充质中表达。此外，在前期成牙本质细胞和成牙本质细胞中可见GDNF和GFRα-1转录本，这表明它们可能参与成牙本质细胞的分化和功能特性的维持。综上所述，这些结果表明GDNF在牙齿神经支配过程中作为一种靶源性神经营养因子发挥作用。此外，GDNF及其受体在牙齿形态发生过程中可能具有非神经元的器官发生功能。
