Role of Chemorepellants during Neural Crest Migration in the Eye

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The molecular signals that guitde cell migration during development and regeneration of the cornea are largely unl<nown. Neural crest cells migrate from the periocular region Into the developing eye and give rise to the cornea stroma and endothelium. Defects In neural crest development are associated wltii Peter's anomaly and Axenfeid-Rieger syndrome, whereas their keratocyte progeny are Involved In the wound healing process that results in scar formation, interactions between the cheoKirepetient SemaphorinSA (SemaSA) and its receptor Neuropllin-1 (Npn-1) are utilized repeatedly throughout development and play a significant role in directing ceil migration and axon projections. However their role during eye development and wound healing has not been examined. We have shown that lens derived SemaSA regulates corneal innervation during development, which is required for the proper partening oif corneal nerves and formation of the ventral plexus. We have also observed that Sema3A and Npn-1 are expressed in the lens and periocular neural crest respectively, early during eye development, but Npn-1 is down-regulated during neural crest migration into the rudimentary eye. Furthermore, Npn-1 and SemaSA are differentially expressed during cornea regeneration. We therefore hypothesize that Sema3/^Npn-1 signaling is important for regulating migration of periocular neural crest and l<eratocytes during cornea development and regeneration. To test this hypothesis, we will combine classical embryological techniques, genetic analysis, molecular biology and video microscopy to examine the role of Npn-1 and SemaSA and visualize neural crest migration in real-time during these events. Experiments will be carried out in chicl< and mouse, as each model offers unique experimental advantages. The following specific aims will be peri'ormed: 1) Examine the migration of neural crest cells Into the cornea by in vivo time-lapse video microscopy. 2) Characterize and examine the role of Npn-1 and SemaSA during mouse eye development. 3) Examine the role of Npn- 1/Sema3A interactions during cornea wound healing.