Role of pioneer neurons in development of peripheral nervous sysytem

嗅觉上皮（OE）在小鼠发育过程中来源于嗅觉基板（OP）。在胚胎期(E) 10.0-E10.5，“早期神经发生”发生在OE，包括从OE迁出的先锋神经元和其他早期分化的神经元的产生。先锋神经元迁移出上颌部，定位于上颌部和前脑之间。先锋神经元是外周神经系统和中枢神经系统在发育过程中的第一个连接。为了揭示控制这种联系的分子机制，我们研究了使用Six1^<-/->产生先锋神经元的基因，因为Six1^<-/->显示先锋神经元及其衍生物完全缺失。我们确定了几个候选基因在Six1下起作用。有趣的是，其中一些与维甲酸信号通路有关。还有一些基因的产物对细胞间的交流很重要，比如Notch和Jagged。同时，我们发现Six1在后期的顶端和基部祖细胞中都有表达。Six1^<-/->未见根尖增生细胞，未见形态可识别的支撑细胞。在Six1^<-/->中，顶端层Notch2和Jagged1的表达与Six1^<-/->一致。Six1^<-/->可见基底层增殖细胞，但未见Ngn1、NeuroD、Notch1、Jagged2的表达。综上所述，Six1调节Notch、Jagged和其他神经源性bHLH转录因子的表达，参与先驱神经元、顶端祖细胞和基底祖细胞的生成。

The olfactory epithelium (OE) is derived from the olfactory placode (OP) during mouse development. At embryonic day (E) 10.0-E10.5, "early neurogenesis" occurs in the OE, which includes production of pioneer neurons that emigrate out of the OE and other early-differentiated neurons. Pioneer neurons migrate out OP/OE and localize between OP/OE and the forebrain. The importance of pioneer neurons are important the first connection between peripheral and central nervous system during the development. To uncover the molecular mechanism that govern this connection, we investigated the genes involved in the production of pioneer neurons using Six1^<-/->, because Six1^<-/-> shows total absence of pioneer neurons and their derivatives. We identified several candidate genes working under Six1. Interestingly, some of them are involved in retinoic acid signaling pathways. Others are genes whose products are important for cell-cell communication, such as Notch and Jagged. In parallel, we found that Six1 is expressed in both apical and basal progenitors at later stages. In Six1^<-/->, 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^<-/->. Basal proliferating cells were observed in Six1^<-/->, but the expression of Ngn1, NeuroD, Notch1, and Jagged2 in the basal layer was absent. In sum, Six1 regulates the expression of Notch, Jagged, and other neurogenic bHLH transcription factors for production of pioneer neurons, apical progenitors, and basal progenitors.