The differential axonal degradation of Ret accounts for cell-type-specific function of glial cell line-derived neurotrophic factor as a retrograde survival factor.
The differential axonal degradation of Ret accounts for cell-type-specific function of glial cell line-derived neurotrophic factor as a retrograde survival factor.
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DOI：
10.1523/jneurosci.5246-09.2010
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发表时间：
2010-04-14
期刊：
影响因子：
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通讯作者：
Pierchala BA
中科院分区：
文献类型：
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作者：
Tsui CC;Pierchala BA
胶质细胞系来源的神经营养因子（GDNF）是一种神经生长因子，对中枢和周围神经元的发育和维持至关重要。GDNF在神经支配的目标中表达，并为几个大的投射神经元群体提供支持。为了确定GDNF是否促进长轴突距离到细胞体的逆行存活，我们采用了分区培养系统。当将GDNF应用于末梢轴突时，仅支持出生后交感神经元适度和短暂的存活，相比之下，在DRG感觉神经元中，GDNF对末梢轴突或细胞体的存活同样有促进作用。Ret， GDNF的酪氨酸激酶受体，在交感神经元轴突中经历了快速的蛋白酶体降解。有趣的是，DRG神经元中激活的Ret水平在轴突中持续存在，也出现在细胞体中，这表明Ret在感觉轴突中没有降解，而是逆行运输。在GDNF刺激下，仅在交感神经元远端轴突抑制蛋白酶体可引起轴突和细胞体中激活Ret的积累。此外，将交感神经元的远端轴突暴露于GDNF和蛋白酶体抑制剂中，但没有一种单独暴露，可以促进强大的存活，与直接应用于细胞体的GDNF相同。这种交感和感觉神经元对目标来源的GDNF的不同反应是由于Ret9和Ret51亚型的不同表达和降解。因此，轴突中Ret的局部降解决定了gfl是否作为逆行存活因子。
Glial cell line-derived neurotrophic factor (GDNF) is a neuronal growth factor critical for the development and maintenance of central and peripheral neurons. GDNF is expressed in targets of innervation and provides support to several populations of large, projection neurons. To determine whether GDNF promotes retrograde survival over long axonal distances to cell bodies, we employed a compartmentalized culture system. GDNF supported only modest and transient survival of postnatal sympathetic neurons when applied to their distal axons, in contrast to DRG sensory neurons in which GDNF promoted survival equally well from either distal axons or cell bodies. Ret, the receptor tyrosine kinase for GDNF, underwent rapid proteasomal degradation in the axons of sympathetic neurons. Interestingly, the level of activated Ret in DRG neurons was sustained in the axons and also appeared in the cell bodies, suggesting that Ret was not degraded in sensory axons and was retrogradely transported. Pharmacologic inhibition of proteasomes only in the distal axons of sympathetic neurons caused an accumulation of activated Ret in both the axons and cell bodies upon GDNF stimulation. Furthermore, exposure of the distal axons of sympathetic neurons to both GDNF and proteasome inhibitors, but neither one alone, promoted robust survival, identical to GDNF applied directly to the cell bodies. This differential responsiveness of sympathetic and sensory neurons to target-derived GDNF was due to the differential expression and degradation of the Ret9 and Ret51 isoforms. Therefore, the local degradation of Ret in axons dictates whether GFLs act as retrograde survival factors.