Role of Homeobox transcription factor encoding gene, Six in peripheral neural network

其中6个基因与果蝇（Drosophila sine oculis，so）同源，在复眼发育中起重要作用。有六个成员的六个基因，从Six 1到Six 6在小鼠中。其中，Six 1和Six 4在小鼠发育过程中在感觉基板、三叉神经节、鳃上神经节和神经嵴细胞中表达。为了了解Six基因在感觉周围神经系统形成中的作用，我们分析了双纯合敲除小鼠（Six 1 ^<-/-> Six 4 ^<-/->）。在基板衍生和神经嵴衍生的颅感觉神经节的发育过程中，在Six 1 ^<-/-> Six 4 ^<-/->中观察到神经发生的早期停滞。上鳃祖细胞不能表达神经生成素1和神经生成素2，这两种神经生成素1和神经生成素2在胚胎第9.5天分别在基板衍生的三叉神经节和上鳃神经节中正常表达并为确定神经元前体所需。NeuroD和Phox 2b基因对神经分化和维持至关重要，也显着减少。此外，在Six 1 ^<-/-> Six 4 ^<-/->中，由于基板源性神经元的正常分化程序不能被激活，导致祖细胞的异常凋亡。我们还观察到Six 1 ^<-/-> Six 4 ^<-/->中基板上皮细胞形成神经节的分层受到干扰。对于神经嵴细胞，野生型和Six 1 ^<-/-> Six 4 ^<-/->中Sox 10在E8.5的表达没有改变，而Six 1 ^<-/-> Six 4 ^<-/->中Sox 10在E10.5的表达严重降低。这些结果表明Six 1 ^<-/-> Six 4 ^<-/->中神经嵴细胞的产生和迁移没有受到干扰，但向胶质细胞的分化受到干扰。总之，我们的数据表明Six 1和Six 4在基板来源的颅感觉神经元的早期分化、分层和存活以及神经嵴细胞的分化中起作用。

Six genes are homologues of the Drosophila sine oculis (so), which plays an essential role in the development of compound eye. There are six members of Six genes, from Six1 to Six6 in mice. Of these, Six1 and Six4 are expressed in sensory placodes, trigeminal ganglion, epibranchial ganglia, and neural crest cells during mouse development. To understand roles of Six genes in formation of sensory peripheral nervous system, we analyzed double homozygous knockout mice (Six1^<-/->Six4^<-/->). During the development of placode-derived and neural crest-derived cranial sensory ganglia, an early arrest of neurogenesis was observed in Six1^<-/->Six4^<-/->. The epibranchial progenitor cells failed to express Neurogenin1 and Neurogenin2, that are normally expressed and required for the determination of neuronal precursors in placodal-derived trigeminal and epibranchial ganglion, respectively at embryonic day (E) 9.5. NeuroD as well as Phox2b genes that are essential for neural differentiation and maintenance, were also dramatically decreased. Moreober, failure to activate normal differentiation program in placodal-derived neurons resulted in abnormal apoptosis of the progenitor cells in Six1^<-/->Six4^<-/->. We also observed that the delamination of placode epithelial cells to form ganglia were disturbed in Six1^<-/->Six4^<-/->. As for neural crest cell, the expression of Sox10 at E8.5 was not altered in wild-type and Six1^<-/->Six4^<-/->, while its expression at E10.5 was severely reduced in Six1^<-/->Six4^<-/->. These results indicated that production and migration of neural crest cells were not disturbed, but differentiation to glial cells were disrupted in Six1^<-/->Six4^<-/->.In sum, our data suggest that Six1 and Six4 play roles for early differentiation, delamination, and survival of the placodally derived cranial sensory neurons and differentiation of neural crest cells.