Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, NJ 08854, USA; Stem Cell Research Center and Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, NJ 08854, USA.
Department of Biology, University of Iowa, CLAS, 214 BB, Iowa City, IA 52242, USA.
Stem Cell Reports. 2017 Nov 14;9(5):1516-1529. doi: 10.1016/j.stemcr.2017.09.011. Epub 2017 Oct 12.
Loss of spiral ganglion neurons (SGNs) significantly contributes to hearing loss. Otic progenitor cell transplantation is a potential strategy to replace lost SGNs. Understanding how key transcription factors promote SGN differentiation in otic progenitors accelerates efforts for replacement therapies. A pro-neural transcription factor, Neurogenin1 (Neurog1), is essential for SGN development. Using an immortalized multipotent otic progenitor (iMOP) cell line that can self-renew and differentiate into otic neurons, NEUROG1 was enriched at the promoter of cyclin-dependent kinase 2 (Cdk2) and neurogenic differentiation 1 (NeuroD1) genes. Changes in H3K9ac and H3K9me3 deposition at the Cdk2 and NeuroD1 promoters suggested epigenetic regulation during iMOP proliferation and differentiation. In self-renewing iMOP cells, overexpression of NEUROG1 increased CDK2 to drive proliferation, while knockdown of NEUROG1 decreased CDK2 and reduced proliferation. In iMOP-derived neurons, overexpression of NEUROG1 accelerated acquisition of neuronal morphology, while knockdown of NEUROG1 prevented differentiation. Our findings suggest that NEUROG1 can promote proliferation or neuronal differentiation.
螺旋神经节神经元（SGNs）的丧失是听力损失的主要原因。耳胚祖细胞移植是一种替代丢失的 SGN 的潜在策略。了解关键转录因子如何促进耳胚祖细胞中的 SGN 分化，加速了替代疗法的研究进展。神经前体细胞转录因子神经基因 1（Neurog1）对 SGN 发育至关重要。本研究利用能够自我更新并分化为耳神经细胞的永生化多能耳胚祖细胞（iMOP）系，发现神经基因 1（Neurog1）在细胞周期蛋白依赖性激酶 2（Cdk2）和神经生成分化 1（NeuroD1）基因的启动子处富集。Cdk2 和 NeuroD1 启动子处 H3K9ac 和 H3K9me3 沉积的变化表明在 iMOP 增殖和分化过程中存在表观遗传调控。在自我更新的 iMOP 细胞中，过表达神经基因 1（Neurog1）增加 CDK2 以促进增殖，而敲低神经基因 1（Neurog1）则降低 CDK2 并减少增殖。在 iMOP 衍生的神经元中，过表达神经基因 1（Neurog1）可加速获得神经元形态，而敲低神经基因 1（Neurog1）则阻止分化。这些结果表明，神经基因 1（Neurog1）可以促进增殖或神经元分化。
