The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
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DOI：
10.1093/brain/awv125
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发表时间：
2015-07-01
期刊：
影响因子：
14.5
通讯作者：
Di Giovanni, Simone
中科院分区：
文献类型：
--
作者：
Joshi, Yashashree;Soria, Marilia Grando;Di Giovanni, Simone
受损的中枢神经系统轴突的再生受到高度限制，导致神经功能障碍。到目前为止，尽管缺乏固有的再生潜力已经被很好地描述，但在中枢神经系统损伤后促进轴突再生和功能恢复的关键调控分子机制仍然是未知的。虽然泛素连接酶在发育过程中和轴突损伤后协调神经元的形态发生和连接，但它们在轴突再生中的具体作用尚不清楚。经过将泛素连接酶与先前定义的轴突再生蛋白相结合的生物信息学网络分析，我们发现由泛素连接酶MDM4、MDM2和转录因子p53(由TP53编码)组成的三联体可能是限制再生程序的中央信号复合体。事实上，在眼睛和脊髓中有条件地删除MDM4或药物抑制MDM2/P53的相互作用可以促进挤压后视神经和脊髓损伤后脊髓上束的轴突再生和发芽。在p53基因缺陷的小鼠中，MDM4-P53的双重条件缺失以及MDM2的抑制阻止了这种再生表型，表明它对P53的依赖。对MDM4缺失的视网膜神经节细胞进行的体外荧光激活细胞分选的全基因组基因表达分析确定了下游靶标IGF1R，其活性和表达被发现是MDM4缺失所引发的再生所必需的。重要的是，我们证明了MDM2/P53-IGF1R轴的药理学增强促进了脊髓损伤后轴突的萌发和功能恢复。因此，我们的结果表明MDM4-MDM2/P53-IGF1R是中枢神经系统再生的原始调控机制，并为促进神经功能恢复提供了新的靶点。
Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.