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Seema Agarwala, Cassidy S Bernstein, anjali ramchandran; BMP Signaling mediates choroid fissure closure by remodeling the retinal epithelium and regulating embryonic vasculature. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6015.
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© ARVO (1962-2015); The Authors (2016-present)
The choroid fissure is a transient ventral midline opening in the developing optic cup, which serves as a gateway for the entering hyaloid vasculature and the exiting optic nerve. A subsequent failure of CF closure (CFC) results in severe ocular abnormalities (Microphthalmia,Anophthalmia, Coloboma), collectively called MAC spectrum disorders. Together, MAC disorders constitute the largest cause of childhood blindness, affecting 5-12/10,000 live births. Defects in BMP signaling cause colobomas in animals and account for 1-2% of all MAC disorders in humans. However, the precise cell behaviors regulated by BMP signaling during CFC remain poorly understood because of the large-scale ocular dysmorphology normally associated with early or broad manipulations of the BMP pathway.
Here, we circumvent these problems by late stage (≥ HH14/E3) BMP manipulations in the chick eye, which produce only moderate colobomas, permitting further analyses.
Our results show that the cell behaviors underlying CFC differ even at short distances across the proximal-distal axis of the optic cup, and differentially respond to BMP signaling. In proximo-medial optic cup, BMPs modulate CF epithelial organization by regulating its dorsal involution, apposition and eventual fusion. More proximally, BMPs mediate the ventral midline invagination of the optic stalk, a morphogenetic event required for correctly localizing the hyaloid vasculature within the optic nerve and directing the optic nerve into the brain. These results suggest that BMP signaling is involved in correctly bending and shaping the optic cup and stalk epithelium during CFC. Interestingly, BMP misexpression also results in increased hyaloid vasculature, which may induce colobomas by acting as a mechanical barrier. However, BMP blockade, which leads to a reduction in hyaloid vasculature, also paradoxically causes colobomas. Thus mechanical and molecular signals from the ingressing hyaloid vasculature may underlie BMP-dependent induction of colobomas.
We conclude that BMP signaling mediates CFC by dynamic modulations of the optic cup epithelium and by regulating the ingression of the hyaloid vasculature.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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