Role of Sixl in development of olfactory epithelium

嗅觉上皮(OE)起源于小鼠发育过程中的嗅觉定位(OP)。在胚胎期(E)10.0-E10.5，“早期神经发生”发生在OE，包括从OE迁出的前驱神经元和其他早期分化的神经元的产生。在E12.5左右，OE组织成成熟的假复层上皮，并显示出“已建立的神经发生”，其中嗅觉感受器神经元(ON)从基底祖细胞分化而来。人们对早期神经发生的分子途径知之甚少。同源结构域蛋白SIX1在所有OP细胞和OE中的神经源性前体中都有表达。在这里，我们表明，尽管在SIX1缺陷小鼠(SIX1^&lt；-/-&gt；)E10.5处Mashl的表达没有改变，但早期神经发生受到严重干扰。在E10.5的SIX1^&lt；-/-&gt；OE中，神经原蛋白1(Ngn1)和神经D的表达水平降低，Hes1和Hes5的表达水平增强。起源于OP/OE的位于OE和前脑之间的间质中的前驱神经元和细胞聚集体在SIX1^&lt；-/-&gt；此外，ORN轴突和促性腺激素释放激素阳性神经元分别无法延伸和迁移到前脑。我们的研究表明，SIX1通过调节Ngn1、NeuroD、Hes1和Hes5在早期神经发生中发挥关键作用。目前，为了更详细地分析前驱神经元产生所必需的基因调控网络，我们计划对E9.5野生型V.S.SIX1；&lt；-/-&OP中相关基因的表达谱进行微阵列分析，确定了前驱神经元分化的候选基因。

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. Around E12.5, the OE becomes organized into mature pseudostratified epithelium and shows "established neurogenesis," in which olfactory receptor neurons (ORNs) are differentiated from basal progenitors. Little is known about the molecular pathway of early neurogenesis. The homeodomain protein Six1 is expressed in all OP cells and neurogenic precursors in the OE. Here we show that early neurogenesis is severely disturbed despite the unaltered expression of Mashl at E10.5 in the Six1-deficient mice (Six1^<-/->). Expression levels of neurogenin1 (Ngn1) and NeuroD are reduced and those of Hes1 and Hes5 are augmented in the OE of Six1^<-/-> at E10.5. Pioneer neurons and cellular aggregates, which are derived from the OP/OE and situated in the mesenchyme between the OE and forebrain, are completely absent in Six1^<-/->. Moreover, ORN axons and the gonadotropin-releasing hormone-positive neurons fail to extend and migrate to the forebrain, respectively. Our study indicates that Six1 plays critical roles in early neurogenesis by regulating Ngn1, NeuroD, Hes1, and Hes5. Currently, to analyze gene regulatory network essential for production of pioneer neurons more detail, we are planning to do microarray analysis of the relative gene expression profiles in E9.5 wild-type v.s. Six1^<-/-> OP identified candidate genes for differentiation of pioneer neurons.