Loss of BMI1 in mature olfactory sensory neurons leads to increased olfactory basal cell proliferation
Loss of BMI1 in mature olfactory sensory neurons leads to increased olfactory basal cell proliferation
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DOI：
10.1002/alr.22366
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发表时间：
2019-06-28
影响因子：
6.4
通讯作者：
Goldstein, Bradley J.
中科院分区：
文献类型：
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作者：
Choi, Rhea;Kurtenbach, Sarah;Goldstein, Bradley J.
嗅裂神经上皮内的嗅感觉神经元（OSNs）的损伤可能与嗅觉丧失有关。虽然它们与鼻腔空气空间的直接接触使OSN容易受伤和死亡，但多种机制维持上皮完整性和嗅觉功能。我们假设，BMI 1，一种富含OSN的多梳蛋白，可能具有神经保护作用。在这里，我们探索了BMI 1在小鼠模型中的功能。方法利用小鼠遗传学方法选择性地删除成熟OSN中的Bmi 1，我们通过免疫组织化学、生物化学和功能测定研究OE稳态的变化。逆转录-定量聚合酶链反应（RT-qPCR），免疫染色和嗅觉电图被用来比较基因表达，细胞组成，嗅觉功能在OSN特异性BMI 1基因敲除小鼠（n = 3至5）和对照组。还进行染色质研究以鉴定BMI 1与其靶基因之间的蛋白质-DNA相互作用（n = 3）。结果OSN特异性BMI 1基因敲除可导致神经元死亡和基底细胞活化增加。染色质的研究表明，增加神经退行性变的机制，由于去抑制的促凋亡基因，p19 ARF。尽管营业额增加，我们发现，嗅神经上皮厚度和嗅觉功能保持完整。我们的研究还揭示了额外的polycomb组蛋白的存在，可以补偿成熟OSN中BMI 1的丢失。结论嗅神经上皮通过多种机制维持上皮内环境的稳定。我们的研究结果提供的证据表明，在BMI 1缺失的小鼠模型中，嗅觉神经上皮的整体完整性和功能没有受到损害，尽管增加了神经元的周转，反映了显着的修复能力，以维持一个关键的感觉系统。
Background Damage to olfactory sensory neurons (OSNs), situated within the neuroepithelium of the olfactory cleft, may be associated with anosmia. Although their direct contact with the nasal airspace make OSNs vulnerable to injury and death, multiple mechanisms maintain epithelium integrity and olfactory function. We hypothesized that BMI1, a polycomb protein found to be enriched in OSNs, may function in neuroprotection. Here, we explored BMI1 function in a mouse model. Methods Utilizing a mouse genetic approach to delete Bmi1 selectively in mature OSNs, we investigated changes in OE homeostasis by performing immunohistochemical, biochemical, and functional assays. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunostaining, and electro-olfactograms were used to compare gene expression, cell composition, and olfactory function in OSN-specific BMI1 knockout mice (n = 3 to 5) and controls. Chromatin studies were also performed to identify protein-DNA interactions between BMI1 and its target genes (n = 3). Results OSN-specific BMI1 knockout led to increased neuron death and basal cell activation. Chromatin studies suggested a mechanism of increased neurodegeneration due to de-repression of a pro-apoptosis gene, p19ARF. Despite the increased turnover, we found that olfactory neuroepithelium thickness and olfactory function remained intact. Our studies also revealed the presence of additional polycomb group proteins that may compensate for the loss of BMI1 in mature OSNs. Conclusion The olfactory neuroepithelium employs multiple mechanisms to maintain epithelial homeostasis. Our findings provide evidence that in a mouse model of BMI1 deletion, the overall integrity and function of the olfactory neuroepithelium are not compromised, despite increased neuronal turnover, reflecting a remarkable reparative capacity to sustain a critical sensory system.