Activity-dependent regulation of axonal growth: posttranscriptional control of the GAP-43 gene by the NMDA receptor in developing hippocampus.
Activity-dependent regulation of axonal growth: posttranscriptional control of the GAP-43 gene by the NMDA receptor in developing hippocampus.
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DOI：
10.1002/(sici)1097-4695(19991105)41:2
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发表时间：
1999-11
期刊：
影响因子：
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通讯作者：
I. Cantallops;A. Routtenberg
中科院分区：
文献类型：
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作者：
I. Cantallops;A. Routtenberg
神经系统的复杂回路已被证明是由活动依赖性过程，往往涉及谷氨酸N-甲基-D-天冬氨酸（NMDA）受体完善。NMDA受体活性与发育过程中的轴突生长和突触可塑性的成人模型直接相关。轴突生长相关蛋白GAP-43参与了与NMDA受体相同的过程，但两者之间的直接联系从未在体内得到证实。NMDA受体可能通过GAP-43调节轴突生长的观点是有吸引力的。我们在海马颗粒细胞长出的轴突（苔藓纤维）中测试了这一想法。颗粒细胞通常只表达GAP-43在一个有组织的由外向内的方式在一个有限的时期在出生后的发展平行的模式轴突延伸。在这里，我们表明，在出生后的发育过程中，在一个转基因小鼠轴承GAP-43启动子/lacZ报告构建体，颗粒细胞也显示出由外向内的模式启动子激活的转基因表达（PATE）的索引。事实上，PATE先于轴突生长，具有时空保真度。由于PATE在生长终止时失活，因此启动子可以作为调节轴突生长的内在程序的开关。在有限的时间范围内（4-8天）给予NMDA受体拮抗剂MK-801导致苔藓纤维染色的程度和强度降低。虽然颗粒细胞中GAP-43 mRNA的水平显著降低，但GAP-43 PATE却没有。GAP-43的表达和轴突生长在发展过程中的水平似乎是双重控制的转录程序，是活性独立的，并通过转录后机制，是活性依赖性和NMDA介导的。
The intricate circuitry of the nervous system has been shown to be refined by activity-dependent processes often involving the glutamate N-methyl-D-aspartate (NMDA) receptor. NMDA receptor activity has been directly associated with axonal growth during development and in adult models of synaptic plasticity. The axonal growth-associated protein GAP-43 has been involved in the same processes as the NMDA receptor, but a direct link between the two has never been demonstrated in vivo. It is attractive to think that the NMDA receptor may regulate axonal growth through GAP-43. We tested this idea in outgrowing axons of hippocampal granule cells, the mossy fibers. Granule cells normally only express GAP-43 in an organized outside-in manner during a restricted period in postnatal development paralleling the pattern of axonal extension. Here, we show that during postnatal development in a transgenic mouse bearing a GAP-43 promoter/lacZ reporter construct, granule cells also display an outside-in pattern of promoter activation as indexed by transgene expression (PATE). In fact, PATE precedes axonal outgrowth with temporospatial fidelity. Since PATE deactivates on growth termination, the promoter may function as a switch for an intrinsic program of regulated axonal growth. The NMDA receptor antagonist MK-801 administered within a restricted time frame (4-8 days) results in a decrease in the extent and intensity of mossy fiber staining. While levels of GAP-43 mRNA are significantly reduced in granule cells, GAP-43 PATE is not. The level of GAP-43 expression and axonal growth during development appears to be dually controlled by a transcriptional program that is activity-independent and by a posttranscriptional mechanism that is activity-dependent and NMDA mediated.