Liu Yiting, Luo Jiangnan, Nässel Dick R
Department of Zoology, Stockholm University Stockholm, Sweden.
Front Mol Neurosci. 2016 Oct 13;9:97. doi: 10.3389/fnmol.2016.00097. eCollection 2016.
Growth of postmitotic neurons occurs during different stages of development, including metamorphosis, and may also be part of neuronal plasticity and regeneration. Recently we showed that growth of post-mitotic neuroendocrine cells expressing the basic helix loop helix (bHLH) transcription factor Dimmed (Dimm) in could be regulated by insulin/IGF signaling and the insulin receptor (dInR). Dimm is also known to confer a secretory phenotype to neuroendocrine cells and can be part of a combinatorial code specifying terminal differentiation in peptidergic neurons. To further understand the mechanisms of function we ectopically expressed Dimm or Dimm together with dInR in a wide range of Dimm positive and Dimm negative peptidergic neurons, sensory neurons, interneurons, motor neurons, and gut endocrine cells. We provide further evidence that dInR mediated cell growth occurs in a Dimm dependent manner and that one source of insulin-like peptide (DILP) for dInR mediated cell growth in the CNS is DILP6 from glial cells. Expressing both Dimm and dInR in Dimm negative neurons induced growth of cell bodies, whereas dInR alone did not. We also found that Dimm alone can regulate cell growth depending on specific cell type. This may be explained by the finding that the dInR is a direct target of Dimm. Conditional gene targeting experiments showed that Dimm alone could affect cell growth in certain neuron types during metamorphosis or in the adult stage. Another important finding was that ectopic Dimm inhibits apoptosis of several types of neurons normally destined for programmed cell death (PCD). Taken together our results suggest that Dimm plays multiple transcriptional roles at different developmental stages in a cell type-specific manner. In some cell types ectopic Dimm may act together with resident combinatorial code transcription factors and affect terminal differentiation, as well as act in transcriptional networks that participate in long term maintenance of neurons which might lead to blocked apoptosis.
有丝分裂后神经元的生长发生在发育的不同阶段，包括变态发育阶段，并且也可能是神经元可塑性和再生的一部分。最近我们发现，在[具体生物或组织]中，表达碱性螺旋-环-螺旋（bHLH）转录因子Dimmed（Dimm）的有丝分裂后神经内分泌细胞的生长可受胰岛素/胰岛素样生长因子（IGF）信号通路和胰岛素受体（dInR）的调节。已知Dimm还能赋予神经内分泌细胞分泌表型，并且可能是指定肽能神经元终末分化的组合密码的一部分。为了进一步了解[具体功能]的机制，我们在多种Dimm阳性和Dimm阴性肽能神经元、感觉神经元、中间神经元、运动神经元和肠道内分泌细胞中异位表达Dimm或Dimm与dInR。我们提供了进一步的证据表明，dInR介导的细胞生长以Dimm依赖的方式发生，并且中枢神经系统中dInR介导的细胞生长的一种胰岛素样肽（DILP）来源是来自神经胶质细胞的DILP6。在Dimm阴性神经元中同时表达Dimm和dInR可诱导细胞体生长，而单独表达dInR则不能。我们还发现，单独的Dimm可根据特定细胞类型调节细胞生长。这可能是因为dInR是Dimm的直接靶点。条件性基因靶向实验表明，单独的Dimm可在变态发育阶段或成年期影响某些神经元类型的细胞生长。另一个重要发现是，异位表达的Dimm可抑制几种通常注定要经历程序性细胞死亡（PCD）的神经元的凋亡。综上所述，我们的结果表明，Dimm在不同发育阶段以细胞类型特异性的方式发挥多种转录作用。在某些细胞类型中，异位表达的Dimm可能与常驻的组合密码转录因子共同作用，影响终末分化，并且还作用于参与神经元长期维持的转录网络，这可能导致凋亡受阻。
