Canonical Notch Signaling Directs the Fate of Differentiating Neurocompetent Progenitors in the Mammalian Olfactory Epithelium
Canonical Notch Signaling Directs the Fate of Differentiating Neurocompetent Progenitors in the Mammalian Olfactory Epithelium
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DOI：
10.1523/jneurosci.0484-17.2018
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发表时间：
2018-05-23
影响因子：
5.3
通讯作者：
Schwob, James E.
中科院分区：
文献类型：
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作者：
Herrick, Daniel B.;Guo, Zhen;Schwob, James E.
成人嗅上皮（OE）在严重上皮损伤后具有完全再生神经感觉和非神经元细胞类型的显着能力。两种干细胞群的终生持续存在支持受损时的 OE 再生：水平基底细胞 (HBC)，处于休眠状态并保留；和球形基底细胞，这是一个异质群体，其中大多数正在活跃分裂。损伤后，这两个群体都能再生 OE 的所有细胞类型，但干细胞池招募后神经元与非神经元谱系定型的机制仍不清楚。我们使用逆转录病毒转导和允许条件性细胞特异性遗传操作以及后代追踪的小鼠系来研究规范Notch信号在确定再生成年OE中神经元与非神经元谱系中的作用。在 HBC 中单独切除 Notch1 或 Notch2 基因不会改变上皮损伤恢复过程中的祖细胞命运，而条件性敲除 Notch1 和 Notch2 一起、逆转录病毒转导具有 MAML 显性失活形式（主脑样）的祖细胞或切除下游辅助因子 RBPJ 会导致后代采取神经元命运 独家。相反，我们发现通过遗传或转导过度表达 Notch1 胞内结构域 (N1ICD) 会完全阻止神经元分化。然而，N1ICD 过表达需要典型辅因子 RBPJ 的两个等位基因来指定下游谱系。总之，我们的结果表明，通过冗余 Notch1 和 Notch2 受体的典型 RBPJ 依赖性 Notch 信号传导对于确定再生成人 OE 中的神经元与非神经元分化是必要且充分的。
The adult olfactory epithelium (OE) has the remarkable capacity to regenerate fully both neurosensory and non-neuronal cell types after severe epithelial injury. Lifelong persistence of two stem cell populations supports OE regeneration when damaged: the horizontal basal cells (HBCs), dormant and held in reserve; and globose basal cells, a heterogeneous population most of which are actively dividing. Both populations regenerate all cell types of the OE after injury, but the mechanisms underlying neuronal versus non-neuronal lineage commitment after recruitment of the stem cell pools remains unknown. We used both retroviral transduction and mouse lines that permit conditional cell-specific genetic manipulation as well as the tracing of progeny to study the role of canonical Notch signaling in the determination of neuronal versus non-neuronal lineages in the regenerating adult OE. Excision of either Notch1 or Notch2 genes alone in HBCs did not alter progenitor fate during recovery from epithelial injury, whereas conditional knock-out of both Notch1 and Notch2 together, retroviral transduction of progenitors with a dominant-negative form of MAML (mastermind-like), or excision of the downstream cofactor RBPJ caused progeny to adopt a neuronal fate exclusively. Conversely, we show that overexpressing the Notch1-intracellular domain (N1ICD) either genetically or by transduction blocks neuronal differentiation completely. However, N1ICD overexpression requires both alleles of the canonical cofactor RBPJ to specify downstream lineage. Together, our results suggest that canonical RBPJ-dependent Notch signaling through redundant Notch1 and Notch2 receptors is both necessary and sufficient for determining neuronal versus non-neuronal differentiation in the regenerating adult OE.