Elucidating signaling networks in Anterior Segment development, repair and diseases

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Defects of the anterior segment (AS) tissue lead to a group of highly debilitating eye disorders referred to as Anterior Segment Dysgenesis (ASD). ASD represents one of the leading causes of congenital corneal opacity and leads to glaucoma in ~50% of the cases and are often associated with myopia. Although few causative genes have been identified, little is known about the molecular and cellular mechanisms underlying tissue malformation in this class of diseases. Several ciliopathies including Meckel, Bardet Biedl, and Joubert syndromes display conditions affecting tissues of the AS including severe myopia. We have recently reported that conditional ablation of the primary cilium in neural crest cells (NCC) leads to ASD in the mouse model with conditions similar to those observed in humans. We have shown that primary cilia of the neural crest derived POM mediate the Hedgehog (Hh) pathway. However, our preliminary results suggest that the cilium could play distinct roles in a tissue specific manner important for AS morphogenesis and repair. The objective of the proposed study is to elucidate the signaling pathways and cellular mechanisms orchestrated by ciliary proteins during morphogenesis of the cornea and other AS structures. Specifically, we will test our central working hypothesis that primary cilia enable neural crest-derived cells of the POM to interpret local morphogenetic cues and elicit distinct cellular behaviors during morphogenesis and repair of different structures of the AS. To test this hypothesis, we have generated specific genetic and computational tools and developed an in vivo imaging approach that will allow us to a) elucidate overlapping and distinct roles of primary cilia and the Hh pathway during the development and repair of AS tissues; b) To identify signaling networks downstream of the primary cilium relevant for AS morphogenesis, and c) conduct a functional characterization of a novel cilia-dependent cell population of the pNC lineage with chondrogenic capabilities. Collectively, the outcome of this work will reveal the integrative role of primary cilia signaling necessary to achieve normal AS morphogenesis. Importantly, delineation of the cilia-related signaling cascades will enable the identification of new therapeutic strategies to treat ASD and trauma.