Parrie Lindsay E, Crowell Jenna A E, Telling Glenn C, Bessen Richard A
Prion Research Center, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, United States.
Prion Research Center, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO, United States.
Dev Biol. 2018 Jun 1;438(1):23-32. doi: 10.1016/j.ydbio.2018.03.012. Epub 2018 Mar 22.
The cellular prion protein (PrP) has been associated with diverse biological processes including cell signaling, neurogenesis, and neuroprotection, but its physiological function(s) remain ambiguous. Here we determine the role of PrP in adult neurogenesis using the olfactory system model in transgenic mice. Olfactory sensory neurons (OSNs) within the olfactory sensory epithelium (OSE) undergo neurogenesis, integration, and turnover even into adulthood. The neurogenic processes of proliferation, differentiation/maturation, and axon targeting were evaluated in wild type, PrP-overexpressing, and PrP-null transgenic mice. Our results indicate that PrP plays a role in maintaining mature OSNs within the epithelium: overexpression of PrP resulted in greater survival of mitotically active cells within the OSE, whereas absence of prion protein resulted in fewer cells being maintained over time. These results are supported by both quantitative PCR analysis of gene expression and protein analysis characteristic of OSN differentiation. Finally, evaluation of axon migration determined that OSN axon targeting in the olfactory bulb is PrP dose-dependent. Together, these findings provide new mechanistic insight into the neuroprotective role for PrP in adult OSE neurogenesis, whereby more mature neurons are stably maintained in animals expressing PrP.
细胞朊蛋白（PrP）与多种生物学过程相关，包括细胞信号传导、神经发生和神经保护，但其生理功能仍不明确。在此，我们利用转基因小鼠的嗅觉系统模型来确定PrP在成体神经发生中的作用。嗅觉感觉上皮（OSE）内的嗅觉感觉神经元（OSN）即使在成年后仍会经历神经发生、整合和更新。我们在野生型、PrP过表达和PrP基因敲除的转基因小鼠中评估了增殖、分化/成熟以及轴突靶向等神经发生过程。我们的结果表明，PrP在上皮内维持成熟OSN方面发挥作用：PrP的过表达导致OSE内有丝分裂活跃细胞的存活率更高，而朊病毒蛋白的缺失则导致随着时间推移维持的细胞数量减少。基因表达的定量PCR分析和OSN分化的蛋白质分析结果均支持了这些结果。最后，对轴突迁移的评估确定，嗅球中OSN轴突的靶向是PrP剂量依赖性的。总之，这些发现为PrP在成年OSE神经发生中的神经保护作用提供了新的机制见解，即在表达PrP的动物中，更成熟的神经元能够得到稳定维持。
