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

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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.