Role of Chemorepellants during Neural Crest Migration in the Eye

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DESCRIPTION (provided by applicant): Despite of their developmental importance and the striking number of visual defects that arise from aberrant neural crest development, little is known of the molecular signals that control their migration during eye development or during the regeneration of the cornea. In the periocular region, neural crest cells express Neuropilin-1 (Npn-1) prior to their migration into the eye, while the lens expresses SemaphorinSA (SemaSA). Interestingly, Npn-1 and SemaSA are also differentially expressed as the cornea regenerates during wound healing. However the role of Npn-1/SemaSA signaling during eye development and wound healing has not been examined. Therefore it is critical to identify and characterize the role of guidance molecules that regulate the migration of periocular neural crest cells and their keratocyte progeny in the cornea. This project will study the role of Npn-1/SemaSA interactions during neural crest migration in the eye. There will be special emphasis on the invasion of periocular neural crest into the eye rudiment, their interaction with the lens and differentiation into corneal endothelium and stroma, and relationship to neural crest-derived keratocytes during regeneration of the cornea. This proposal combines classical embryological techniques with molecular biology and video microscopy to visualize neural crest migration in real-time and examine the role of Npn-1 and SemaSA during these events. Experiments will be carried out in chick and mouse, as each model offers unique experimental advantages. The following specific aims will be performed: 1) Examine the role of Npn-1/SemaSA interactions during neural crest contribution to the cornea in vivo and in vitro. 2) Examine the migration of neural crest cells into the cornea by in vivo time-lapse video microscopy. 3) Characterize the expression of Npn-1 and SemaSA during mouse eye development. 4) Examine the role of Npn-1/SemaSA interactions during mouse eye development. 5) Examine the role of Npn-1/SemaSA interactions during cornea wound healing. Significance: The proposed research aims to provide an insight into the role of guidance molecules during neural crest migration into the eye during development and of their keratocyte progeny during cornea regeneration. Understanding the role of guidance molecules during -these processes may provide clues on how the migration pattern of neural crest cells is disrupted in congenital eye disorders.