Ha Taejeong, Moon Kyeong Hwan, Dai Le, Hatakeyama Jun, Yoon Keejung, Park Hee-Sae, Kong Young-Yoon, Shimamura Kenji, Kim Jin Woo
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, South Korea.
Department of Brain Morphogenesis, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
Cell Rep. 2017 Apr 11;19(2):351-363. doi: 10.1016/j.celrep.2017.03.040.
Notch signaling in neural progenitor cell is triggered by ligands expressed in adjacent cells. To identify the sources of active Notch ligands in the mouse retina, we negatively regulated Notch ligand activity in various neighbors of retinal progenitor cells (RPCs) by eliminating mindbomb E3 ubiquitin protein ligase 1 (Mib1). Mib1-deficient retinal cells failed to induce Notch activation in intra-lineage RPCs, which prematurely differentiated into neurons; however, Mib1 in post-mitotic retinal ganglion cells was not important. Interestingly, Mib1 in the retinal pigment epithelium (RPE) also contributed to Notch activation in adjacent RPCs by supporting the localization of active Notch ligands at RPE-RPC contacts. Combining this RPE-driven Notch signaling and intra-retinal Notch signaling, we propose a model in which one RPC daughter receives extra Notch signals from the RPE to become an RPC, whereas its sister cell receives only a subthreshold level of intra-retinal Notch signal and differentiates into a neuron.
神经祖细胞中的Notch信号由相邻细胞表达的配体触发。为了确定小鼠视网膜中活性Notch配体的来源，我们通过消除mindbomb E3泛素蛋白连接酶1（Mib1），对视网膜祖细胞（RPC）的各种相邻细胞中的Notch配体活性进行了负调控。Mib1缺陷的视网膜细胞未能在谱系内RPC中诱导Notch激活，这些RPC过早分化为神经元；然而，有丝分裂后视网膜神经节细胞中的Mib1并不重要。有趣的是，视网膜色素上皮（RPE）中的Mib1也通过支持活性Notch配体在RPE-RPC接触处的定位，促进了相邻RPC中的Notch激活。结合这种RPE驱动的Notch信号和视网膜内Notch信号，我们提出了一个模型，其中一个RPC子代从RPE接收额外的Notch信号以成为RPC，而其姐妹细胞仅接收亚阈值水平的视网膜内Notch信号并分化为神经元。
