Merianda Tanuja T, Coleman Jennifer, Kim Hak Hee, Kumar Sahoo Pabitra, Gomes Cynthia, Brito-Vargas Paul, Rauvala Heikki, Blesch Armin, Yoo Soonmoon, Twiss Jeffery L
Department of Anatomy and Neurobiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129.
Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803.
J Neurosci. 2015 Apr 8;35(14):5693-706. doi: 10.1523/JNEUROSCI.3397-14.2015.
High mobility group (HMG) proteins concentrate in the nucleus, interacting with chromatin. Amphoterin is an HMG protein (HMGB1) that has been shown to have extranuclear functions and can be secreted from some cell types. Exogenous amphoterin can increase neurite growth, suggesting that the secreted protein may have growth promoting activities in neurons. Consistent with this, we show that depletion of amphoterin mRNA from cultured adult rat DRG neurons attenuates neurite outgrowth, pointing to autocrine or paracrine mechanisms for its growth-promoting effects. The mRNA encoding amphoterin localizes to axonal processes and we showed recently that its 3'-UTR is sufficient for axonal localization of heterologous transcripts (Donnelly et al., 2013). Here, we show that amphoterin mRNA is transported constitutively into axons of adult DRG neurons. A preconditioning nerve injury increases the levels of amphoterin protein in axons without a corresponding increase in amphoterin mRNA in the axons. A 60 nucleotide region of the amphoterin mRNA 3'-UTR is necessary and sufficient for its localization into axons of cultured sensory neurons. Amphoterin mRNA 3'-UTR is also sufficient for axonal localization in distal axons of DRG neurons in vivo. Overexpression of axonally targeted amphoterin mRNA increases axon outgrowth in cultured sensory neurons, but axon growth is not affected when the overexpressed mRNA is restricted to the cell body.
高迁移率族（HMG）蛋白集中于细胞核内，与染色质相互作用。两性调节蛋白是一种HMG蛋白（HMGB1），已被证明具有核外功能，并且可以从某些细胞类型中分泌出来。外源性两性调节蛋白可以增加神经突生长，这表明分泌的蛋白可能在神经元中具有促进生长的活性。与此一致的是，我们发现从培养的成年大鼠背根神经节（DRG）神经元中去除两性调节蛋白mRNA会减弱神经突的生长，这表明其促进生长的作用存在自分泌或旁分泌机制。编码两性调节蛋白的mRNA定位于轴突，并且我们最近表明其3'-非翻译区（UTR）足以使异源转录本定位于轴突（唐纳利等人，2013年）。在这里，我们表明两性调节蛋白mRNA持续运输到成年DRG神经元的轴突中。预处理的神经损伤会增加轴突中两性调节蛋白的水平，而轴突中两性调节蛋白mRNA却没有相应增加。两性调节蛋白mRNA 3'-UTR的一个60个核苷酸的区域对于其定位于培养的感觉神经元的轴突是必要且充分的。两性调节蛋白mRNA 3'-UTR对于体内DRG神经元远端轴突的轴突定位也是足够的。轴突靶向的两性调节蛋白mRNA的过表达增加了培养的感觉神经元中的轴突生长，但当过表达的mRNA仅限于细胞体时，轴突生长不受影响。
