Abnormal Craniofacial Morphogenesis of the Small Eye Rat

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Craniofacial Morphogenesis of vertebrates includes complex processes such as formation of the neural tube, migration and differentiation of neural crest cells, and development of sensory organs and nervous systems. Any failures in these developmental processes result in various congenital deseases, e.g., excencephaly, cleft lip and palate, micrognathia ; malformed teeth etc. In the present research project, we used a mutant rat strain called Small eye rat (rSey2) as a good model for analyzing craniofacial morpho-genesis in mammals. The Small eye rat has a mutation in Pax6 gene encoding a transcription factor. Pax6 is originally cloned by homology with Drosophila gene called paired. Homozygous new born has no eyes and no nose and exhibit severe craniofacial malformations. We identified that impaired migration of midbrain crest cells into the frontonasal mass leads to dysplasia of nasal cartilage and related facial bones. Pax6 gene expression is absent from the crest cells but positive i … More n the frontonasal epithelium, i.e., the pathway for midbrain crest cells. Normal crest cells isolated fromthe wild-type midbrain failed to migrate into the frontonasal mass in the host mutant embryos. Therefore, Pax6 is suggested to influence the midbrain crest cell migration toward the frontonasal mass in a cell non-autonomous mechanism. We also found that LewisX is distributed in the frontonasal epithelium of the wild type embryos, while it is absent from the mutant epithelium. Instead, the frontonasal epithelium of the mutant expressed HNK-1 epitope, which shares a common precursor with LewisX.Biochemical analyses showed that enzyme activity of fucosyltransferase, which is involved in synthesis of Lewis X, was drastically lower in the homozygotes. Among various genes encoding fucosyltransferases, we identified that expression of FucT IX, a novel fucosyltransferase gene, is specifically lost in the mutant. From these results, Pax6 is suggested to be important in craniofacial morphogenesis through controling migration of midbrain crest cells toward the frontnasal mass. Less