Ikeda Keiko, Kageyama Ryoichiro, Suzuki Yuko, Kawakami Kiyoshi
Division of Biology, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Int J Dev Biol. 2010;54(10):1453-64. doi: 10.1387/ijdb.093041ki.
The rodent olfactory epithelium (OE) is a good model system for studying the principles of stem and progenitor cell biology, because of its capacity for continuous neurogenesis throughout life and relatively well-characterized neuronal lineage. The development of mouse OE is divided into two stages, early and established neurogenesis. In established neurogenesis, which starts at embryonic day (E) 12.5, sustentacular cells and olfactory receptor neurons (ORNs) are produced from apical and basal progenitors, respectively. We previously reported that Six1(-/-) shows a lack of mature ORNs throughout development and disorganization of OE after E12.5. However, the molecular bases for these defects have not been addressed. Here, we show that Six1 is expressed in both apical and basal progenitors. In Six1(-/-) mice, apical proliferating cells were absent and no morphologically identifiable sustentacular cells were observed. Consistently, the expression of Notch2 and Jagged1 in the apical layer was absent in Six1(-/-) mice. On the other hand, basal proliferating cells were observed in Six1(-/-) animals, but the expression of Ngn1, NeuroD, Notch1, and Jagged2 in the basal layer was absent. The expression of Mash1, the determination gene for ORNs, and Hes genes was enhanced in Six1(-/-) mice. The present findings suggest that Six1 regulates production of functional apical and basal progenitors during OE development, through the regulation of various genes, such as neuronal basic helix-loop-helix (bHLH), neuronal repressor bHLH, and genes involved in the Notch signaling pathway.
啮齿动物的嗅觉上皮（OE）是研究干细胞和祖细胞生物学原理的良好模型系统，因为它在整个生命过程中具有持续神经发生的能力，并且神经元谱系相对特征明确。小鼠OE的发育分为两个阶段，即早期神经发生和成熟神经发生。在始于胚胎第12.5天（E12.5）的成熟神经发生过程中，支持细胞和嗅觉受体神经元（ORN）分别由顶端祖细胞和基底祖细胞产生。我们之前报道Six1基因敲除小鼠（Six1(-/-)）在整个发育过程中缺乏成熟的ORN，且在E12.5之后OE出现紊乱。然而，这些缺陷的分子基础尚未得到阐明。在此，我们发现Six1在顶端祖细胞和基底祖细胞中均有表达。在Six1(-/-)小鼠中，顶端增殖细胞缺失，未观察到形态上可识别的支持细胞。同样，Six1(-/-)小鼠顶端层中Notch2和Jagged1的表达缺失。另一方面，在Six1(-/-)动物中观察到基底增殖细胞，但基底层中Ngn1、NeuroD、Notch1和Jagged2的表达缺失。ORN的决定基因Mash1和Hes基因在Six1(-/-)小鼠中的表达增强。目前的研究结果表明，Six1通过调控各种基因，如神经元碱性螺旋-环-螺旋（bHLH）、神经元抑制性bHLH以及参与Notch信号通路的基因，在OE发育过程中调节功能性顶端和基底祖细胞的产生。
