Chen Jie, Laramore Cindy, Shifman Michael I
Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA 19140, USA.
Shriners Hospitals Pediatric Research Center (Center for Neural Repair and Rehabilitation), Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA 19140, USA; Department of Neuroscience, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA 19140, USA.
Exp Neurol. 2016 Jun;280:50-9. doi: 10.1016/j.expneurol.2016.04.001. Epub 2016 Apr 5.
After spinal cord injury (SCI) in mammals, injured axons fail to regenerate. By contrast, lampreys recover from complete spinal transection and axons regenerate selectively in their correct paths. Yet the large, identified reticulospinal neurons in the lamprey brain vary greatly in their regenerative abilities - some have high regeneration capacity (probability of regeneration >50%) and others have low regeneration capacity (<30%) - even though they have similar projection paths. The presence of both regenerating and non-regenerating neurons located in the same brain region and projecting to the same axon tracts suggests that differences in their regenerating abilities depend upon factors intrinsic to the neurons. Previous work has suggested that axon regeneration, especially in PNS, could depend on epigenetic mechanisms of histone modifications, such as the acetylation of histone tails. Our data indicated that expression of the enzymes responsible for regulating the acetylation of histone (KATs and HDACs) - KAT2A, KAT5 and P300 and HDAC3 did not change after SCI in either high regeneration capacity or low regeneration capacity neurons. In the present report, we show a novel and unexpected relationship between neuron regeneration abilities and expression of HDAC1. While HDAC1 expression was downregulated in both high and low regeneration capacity neurons 2 and 4weeks after SCI, it was upregulated at 7weeks at almost all RS neurons. However, at 10weeks post-transection only high regeneration capacity neurons displayed elevated HDAC1 mRNA expression and HDAC1 expression was again downregulated in low regeneration capacity neurons. Moreover, we show that HDAC1 is preferentially expressed in regenerated neurons, but not in non-regenerating neurons. Together, these results suggest that SCI causes significant changes in HDAC1 expression and that HDAC1 expression in regenerating neurons may modulates a survival or regeneration programs.
在哺乳动物脊髓损伤（SCI）后，受损轴突无法再生。相比之下，七鳃鳗能从完全性脊髓横断中恢复，并且轴突会沿着正确路径选择性再生。然而，七鳃鳗脑中已明确的大型网状脊髓神经元的再生能力差异很大——一些具有高再生能力（再生概率>50%），而另一些再生能力低（<30%）——尽管它们具有相似的投射路径。位于同一脑区且投射至相同轴突束的再生神经元和非再生神经元的存在表明，它们再生能力的差异取决于神经元内在的因素。先前的研究表明，轴突再生，尤其是在周围神经系统中，可能依赖于组蛋白修饰的表观遗传机制，例如组蛋白尾部的乙酰化。我们的数据表明，在高再生能力或低再生能力的神经元中，脊髓损伤后负责调节组蛋白乙酰化的酶（KATs和HDACs）——KAT2A、KAT5、P300和HDAC3的表达均未发生变化。在本报告中，我们展示了神经元再生能力与HDAC1表达之间一种新颖且意想不到的关系。虽然脊髓损伤后2周和4周，高再生能力和低再生能力的神经元中HDAC1表达均下调，但在7周时，几乎所有网状脊髓神经元的HDAC1表达均上调。然而，横断后10周，只有高再生能力的神经元显示HDAC1 mRNA表达升高，而低再生能力的神经元中HDAC1表达再次下调。此外，我们表明HDAC1在再生神经元中优先表达，而在非再生神经元中不表达。总之，这些结果表明脊髓损伤会导致HDAC1表达发生显著变化，并且再生神经元中的HDAC1表达可能会调节生存或再生程序。
