The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons.
The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons.
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DOI：
10.1016/j.mcn.2015.08.008
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发表时间：
2015-09
期刊：
影响因子：
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通讯作者：
Blackmore MG
中科院分区：
文献类型：
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作者：
Simpson MT;Venkatesh I;Callif BL;Thiel LK;Coley DM;Winsor KN;Wang Z;Kramer AA;Lerch JK;Blackmore MG
胚胎和周围神经系统中的神经元通过激活支持轴突生长的转录程序对损伤做出反应，最终导致功能恢复。相比之下，成人中枢神经系统（CNS）的神经元在损伤后轴突再生能力有限，从根本上限制了修复。激活中枢神经系统神经元的促再生基因表达是一种很有前途的治疗方法，但由于对相关转录因子的不完全了解，进展受到阻碍。一个新兴的假设是，与神经系统外的细胞生长和运动有关的因素也可能控制神经元轴突的生长。因此，我们在神经突生长试验中测试了69种转录因子，这些转录因子先前在非神经元细胞中被鉴定为具有肿瘤抑制或致癌特性。该筛选发现YAP1和E2F1是神经突生长的促进因子，PITX1、RBM14、ZBTB16和HHEX是抑制因子。后续实验集中于肿瘤抑制因子HHEX，这是最强的生长抑制剂之一。HHEX在脊髓损伤后的成人中枢神经系统神经元（包括皮质脊髓束神经元）中广泛表达，但在未成熟皮质神经元和成人外周神经元中仅微量表达。出生后早期皮层神经元中HHEX的过表达降低了轴突的初始发生和轴突的延伸率，结构域缺失分析强烈暗示转录抑制是其潜在的机制。这些发现提示HHEX在发育中的中枢神经系统中限制轴突生长的作用，并证实了先前确定的癌基因和肿瘤抑制因子在轴突延伸中发挥保守作用的假设。
Neurons in the embryonic and peripheral nervous system respond to injury by activating transcriptional programs supportive of axon growth, ultimately resulting in functional recovery. In contrast, neurons in the adult central nervous system (CNS) possess a limited capacity to regenerate axons after injury, fundamentally constraining repair. Activating pro-regenerative gene expression in CNS neurons is a promising therapeutic approach, but progress is hampered by incomplete knowledge of the relevant transcription factors. An emerging hypothesis is that factors implicated in cellular growth and motility outside the nervous system may also control axon growth in neurons. We therefore tested sixty-nine transcription factors, previously identified as possessing tumor suppressive or oncogenic properties in non-neuronal cells, in assays of neurite outgrowth. This screen identified YAP1 and E2F1 as enhancers of neurite outgrowth, and PITX1, RBM14, ZBTB16, and HHEX as inhibitors. Follow-up experiments focused on the tumor suppressor HHEX, one of the strongest growth inhibitors. HHEX is widely expressed in adult CNS neurons, including corticospinal tract neurons after spinal injury, but is present in only trace amounts in immature cortical neurons and adult peripheral neurons. HHEX overexpression in early postnatal cortical neurons reduced both initial axonogenesis and the rate of axon elongation, and domain deletion analysis strongly implicated transcriptional repression as the underlying mechanism. These findings suggest a role for HHEX in restricting axon growth in the developing CNS, and substantiate the hypothesis that previously identified oncogenes and tumor suppressors can play conserved roles in axon extension.