神經生長發育初期需要指引因子(guidance cues)或基質結合分子(substrate-bound molecules)與神經生長錐(nerve growth cone)的接受器結合，接著經由一連串的訊息傳遞路徑造成細胞骨架的重新排列，最終改變軸突的生長方向。雖然在胚胎發育時期運動神經與肌細胞形成突觸的過程中胰島素樣生長因子(Insulin-like growth factor-1，IGF-1)扮演重要的角色；根據研究也發現，胚胎發育時期骨骼肌細胞中IGF-1表現量相當高，直到神經-肌突觸建立完成後IGF-1的表現量才會下降。然而，IGF-1對於胚胎發育早期運動神經生長方向是否具有導引作用，目前還是不清楚的。
在本實驗中，主要探討IGF-1在胚胎發育時期造成神經生長錐偏轉現象(growth cone turning)，以及訊息傳遞路徑。我們利用非洲爪蟾(Xenopus Laevis)的神經培養，以turning assay的實驗方式來探討單一特定分子IGF-1對axon guidance生長呈現趨向(attraction)或逆向(repulsion)的分布。在turning assay是使用細胞培養後4至10小時(胚胎發育時期)和24小時(成熟時期)的culture。注射用玻璃毛細管(直徑約 1 μm)以每秒1次，每次50 msec duration的給藥方式來進行實驗。
研究結果顯示IGF-1注射下，胚胎發育時期神經生長速率較成熟時期神經快，且轉彎角度(turning angle)也較明顯朝向注射方向偏轉。預處理IGF-1接受器的抑制劑Genistein (tyrosine kinase inhibitor)可以阻斷IGF-1所造成神經受到吸引而產生偏轉，顯示IGF-1造成的growth cone turning是透過IGF-1 receptor的活化，引起下游訊息傳遞路徑，最後造成神經偏轉現象。另外針對鈣離子(Calcium)的來源，在Ca2+-free溶液置換和鎘離子(CdCl2)預處理下，結果發現皆影響IGF-1對神經產生的偏轉作用，顯示鈣離子的流入需要透過voltage-activated calcium channels提共。在細胞內儲存池IP3R利用Xec抑制劑預處理，會阻止原本IGF-1對神經產生的偏轉作用。分別預處理PI 3-kinase抑制劑wortmannin和phospholipase Cγ (PLCγ)抑制劑U73122皆會影響IGF-1對神經吸引轉向的作用。此外，IGF-1對神經偏轉作用也會受到TRP channels的抑制劑SKF96365或Gadolinium (Gd3+)的處理而減少，顯示細胞內鈣離子參與其中的訊息調控。綜合以上所述，我們的研究顯示IGF-1吸引神經的偏轉作用是透過PLCγ,IP 3-kinase以及TRP channels的訊息傳遞路徑所調控。

The path-finding of developing neurons subject to the guidance of both attractive and repulsive cues emerge in the way to their target. The discoveries of IGF-1 (insulin-like growth factor-1) expression in the developing skeletal muscle increase with the formation of differentiated skeletal muscle fibers and decrease to very low adult levels during the process of synapse elimination. Although evidence suggests that insulin-like growth factor plays an important role in the development and growth of the neuromuscular synapse, the effect of IGF-1 in the guidance on the growth cone of a motoneuron remains unknown. Here we focus on the possibility and underlying molecular mechanisms of IGF-1 in the guidance of a developing neuron by using 4 to 10 hours (embryonic development) and 1-day-old (mature stage) primary cultured motoneurons of Xenopus laevis.
The growth rate of developing axons was increased and the growth cones were significantly attracted toward to the direction of IGF-1 application. Pretreatment of tyrosine kinase inhibitor genistein effectively occluded growth turning response induced by IGF-1. The IGF-1-induced guidance effect was abolished when calcium was eliminated from the culture medium or bath application with the pharmacological calcium channel inhibitor cadmium, indicating that calcium influxes through voltage-activated calcium channels is required. IP3 receptor Xec hampered the IGF-1-induced turning. Treating cells with PI-3 kinase inhibitor wortmannin and with phospholipase Cγ (PLCγ) inhibitor U73122 abolished IGF-1-induced axonal attraction. Moreover, IGF-1-induced turning response is significantly occluded by store depletion-activated calcium channel (TRPC) inhibitors either SKF96369 or Gadolinium, suggesting the involvement of internal calcium store. Overall, results from our studies demonstrate IGF-1 has an attractive effect on axonal guidance and this is done via PLCγ, PI3 kinase and TRPC signaling cascades.

論文審定書 i
致謝 ii
中文摘要 iii
Abstract v
目錄 vii
圖目錄 viii
附圖目錄 x
縮寫表 xi
緒論 1
實驗目的 8
實驗材料 9
實驗方法 12
結果 19
討論 29
參考文獻 35
Figure 1. Experimental design of pressure injection-induced microscopic gradient. 45
Figure 2. Cyclic AMP microscopic gradient successfully induce attractive response on growth cone of Xenopus developing motoneuron. 47
Figure 3. Attractive effect of IGF-1 on Xenopus developing spinal motoneuron. 49
Figure 4. Effect of IGF-1-induced attractive turning response on Xenopus motoneuron at different developmental stages. 51
Figure 5. Role of calcium on IGF-1-induced growth cone turning. 53
Figure 6. Involvement of internal calcium reservoir in IGF-1-induced growth cone turning response. 55
Figure 7. The exocytic membrane effect of IGF-1 microscopic gradient on the growth cone. 56
Figure 8. Role of ryanodine receptor in IGF-1-induced attractive turning response. 58
Figure 9. IP3 receptor is responsible for IGF-1-induced turning response at developing Xenopus motoneuron. 60
Figure 10 . Activation of tyrosine kinase IGF-1 receptor is prerequisite for IGF-1-induced growth cone turning response. 62
Figure 11. PLCγ activity is involvement in IGF-1-induced growth cone turning. 64
Figure 12. Involvement of PI-3 kinase pathway in IGF-1-induced growth cone turning. 66
Figure 13. Role of MAP kinase in growth cone turning response induced by IGF-1. 68
Figure 14. Summary of the effect of pharmacological inhibitors on IGF-1-induced growth cone turning response. 70
Figure 15. TRPC channel is involved in IGF-1-induced growth cone turning response. 72
Figure 16. Effect of TPR channel inhibitor Gd3+ on the growth cone turning response induced by IGF-1. 74
Figure 17. Schematic diagram illustrating in the signaling cascade underlying IGF-1-induced attractive growth cone turning response. 77
Table 1. 75

附圖 1. The structure of the growth cone. 79
附圖 2. Chemorepulsion and chemoattraction. 80
附圖 3. Structure of the insulin receptor and IGF-I receptor. 81
附圖 4. Representation of the expression profiles of IGFs. 82
附圖 5. The system of pharmacy appliction with air pump. 83
附圖 6. Procedures for the preparing Xenopus nerve culture. 84

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