Abstract
Epithelial fusion underlies many vital organogenic processes during embryogenesis. Disruptions to these cause a significant number of human birth defects, including ocular coloboma. We provide robust spatial-temporal staging and unique anatomical detail of optic fissure closure (OFC) in the embryonic chick, including evidence for roles of apoptosis and epithelial remodelling. We performed complementary transcriptomic profiling and show that Netrin-1 (NTN1) is precisely expressed in the chick fissure margin during fusion but is immediately downregulated after fusion. We further provide a combination of protein localisation and phenotypic evidence in chick, humans, mice and zebrafish that Netrin-1 has an evolutionarily conserved and essential requirement for OFC, and is likely to have an important role in palate fusion. Our data suggest that NTN1 is a strong candidate locus for human coloboma and other multi-system developmental fusion defects, and show that chick OFC is a powerful model for epithelial fusion research.
Highlights
Fusion of epithelia is an essential process during normal human development and its dysregulation can result in birth defects affecting the eye, heart, palate, neural tube, and multiple other tissues (Ray and Niswander, 2012)
A recent study reported that the proximal chick optic fissure margin (OFM) closes via the intercalation of incoming astrocytes and the outgoing optic nerve (Bernstein et al, 2018), in a process that does not reflect the epithelial fusion seen during human optic fissure closure (OFC)
This study provides the first detailed report of epithelial fusion during chick OFC and illustrates the power of the embryonic chick eye to investigate the mechanisms guiding this important developmental process further and to provide insights into human eye development and broader fusion contexts
Summary
Fusion of epithelia is an essential process during normal human development and its dysregulation can result in birth defects affecting the eye, heart, palate, neural tube, and multiple other tissues (Ray and Niswander, 2012). Ocular coloboma (OC) is a structural eye defect that presents as missing tissue or a gap in the iris, ciliary body, choroid, retina and/or optic nerve It arises from a failure of fusion at the optic fissure (OF; referred to as the choroid fissure) in the ventral region of the embryonic eye cup early in development (Patel and Sowden, 2019; Onwochei et al, 2000; Gregory-Evans et al, 2004)
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