Sirtuin 6 (SIRT6), a member of the Sirtuin family, acts as nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, mono-adenosine diphosphate (ADP)-ribosyltransferase, and fatty acid deacylase, and plays critical roles in inflammation, aging, glycolysis, and DNA repair. Accumulating evidence has suggested that SIRT6 is involved in brain functions such as neuronal differentiation, neurogenesis, and learning and memory. However, the precise molecular roles of SIRT6 during neuronal circuit formation are not yet well understood. In this study, we tried to elucidate molecular roles of SIRT6 on neurite development by using primary-cultured hippocampal neurons. We observed that SIRT6 was abundantly localized in the nucleus, and its expression was markedly increased during neurite outgrowth and synaptogenesis. By using shRNA-mediated SIRT6-knockdown, we show that both dendritic length and the number of dendrite branches were significantly reduced in the SIRT6-knockdown neurons. Microarray and subsequent gene ontology analysis revealed that reducing SIRT6 caused the downregulation of immediate early genes (IEGs) and alteration of several biological processes including MAPK (ERK1/2) signaling. We found that nuclear accumulation of phosphorylated ERK1/2 was significantly reduced in SIRT6-knockdown neurons. Overexpression of SIRT6 promoted dendritic length and branching, but the mutants lacking deacetylase activity had no significant effect on the dendritic morphology. Collectively, the presented findings reveal a role of SIRT6 in dendrite morphogenesis, and suggest that SIRT6 may act as an important regulator of ERK1/2 signaling pathway that mediates IEG expression, which leads to dendritic development.

Sirtuin 6 (SIRT6) 是 Sirtuin 家族的一员，作为烟酰胺腺嘌呤二核苷酸 (NAD) 依赖性蛋白脱乙酰酶、二磷酸单腺苷 (ADP)-核糖基转移酶和脂肪酸脱酰酶，在炎症、衰老、糖酵解和 DNA 修复。越来越多的证据表明 SIRT6 参与大脑功能，如神经元分化、神经发生以及学习和记忆。然而，SIRT6 在神经元回路形成过程中的精确分子作用尚不清楚。在这项研究中，我们试图通过使用原代培养的海马神经元阐明 SIRT6 对神经突发育的分子作用。我们观察到 SIRT6 大量位于细胞核中，并且在神经突生长和突触发生过程中其表达显着增加。通过使用 shRNA 介导的 SIRT6 击倒，我们表明树突长度和树突分支的数量在 SIRT6 击倒神经元中均显着减少。微阵列和随后的基因本体分析表明，减少 SIRT6 会导致立即早期基因 (IEG) 的下调和包括 MAPK (ERK1/2) 信号在内的几种生物过程的改变。我们发现磷酸化 ERK1/2 的核积累在 SIRT6 敲低神经元中显着减少。SIRT6 的过表达促进了树突长度和分枝，但缺乏脱乙酰酶活性的突变体对树突形态没有显着影响。总的来说，所提出的发现揭示了 SIRT6 在树突形态发生中的作用，