Abnormal migration and distribution of neural crest cells in Pax6 heterozygous mutant eye, a model for human eye diseases

PAX6/Pax6 gene encodes a transcription factor that is crucially required for eye development. Pax6 heterozygous mutant mouse (Pax6(Sey/+)) shows various ocular defects, especially in the anterior segment. It has been well known that the induction of the lens and development of the cornea and retina are dependent on PAX6/Pax6 in a cell-autonomous fashion, although the influence of PAX6/Pax6 on the other tissues derived from the ocular mesenchyme is largely unknown. Using transgenic mouse lines in which neural crest cells are genetically marked by LacZ or EGFP, we revealed the extensive contribution of neural crest derived cells (NCDCs) to the ocular tissues. Furthermore, various eye defects in Pax6(Sey/+) mouse were accompanied by abnormal distribution of NCDCs from early developmental stages to the adult. In Pax6(Sey/+) mouse mice, neural crest cells abnormally migrated into the developing eye in a cell nonautonomous manner at early embryonic stages. These results indicate that normal distribution and integration of NCDCs in ocular tissues depend on a proper dosage of Pax6, and that Pax6(Sey/+) eye anomalies are caused by cell autonomous and nonautonomous defects due to Pax6 haploinsufficiency.