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Benjamen A Filas, Jie Huang, Larry A Taber, David C Beebe; Mechanics of Optic Fissure Invagination. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4462.
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© ARVO (1962-2015); The Authors (2016-present)
During early eye development the ventral optic cup invaginates to form the optic fissure. Defects in invagination have usually been studied because the deletion or mutation of a gene induces a mutant phenotype (e.g. severe coloboma, or failure of hyaloid artery and/or optic nerve formation). However, the morphogenetic mechanisms that drive optic fissure formation (and malformation) are unknown.
The optic fissure of developing chicken (HH13-21) and mouse embryos (E9.5-12.5) was non-invasively imaged using an optical coherence tomography system coupled to a Nikon FN1 microscope (Thorlabs). Optic cups were segmented using the Computerized Anatomy Reconstruction Toolkit and surface curvature was computed and mapped to the 3-D reconstructions with a custom Matlab routine. A finite-element plane-strain model (Comsol Multiphysics, v4.2) was used to simulate volumetric growth in the ventral optic cup assuming a Blatz-Ko pseudoelastic strain energy density function. Regional proliferation rates were specified from morphological measurements made using ImageJ.
OCT images showed that optic fissure invagination was distinct; occurring after optic cup formation was complete (Fig. 1, top). This invagination was asymmetric in transverse section and characterized by epithelial elongation (up to 50%) (Fig. 1, middle). Next, the fissure narrowed and deepened prior to closure (Fig. 1, bottom). Noting that Morcillo et al. (Development, 133: 3179-3190, 2006) found reduced cell proliferation in the ventral optic cup of Bmp7 KOs (fissure invagination blocked), and that we have found reduced cell proliferation in optic vesicle Bmp4 KOs (fissure and optic cup formation blocked, unpublished), we hypothesized regional growth as a mechanism for fissure formation. To test this, we used a finite-element model to simulate increased transverse growth on the nasal vs. temporal side of the fissure, as guided by morphology measurements. Resulting model shapes and curvatures were similar to experiments throughout the invagination process (Fig. 1, bottom).
Morphological and computational analysis suggests differential growth to be a driver of fissure invagination. This finding is corroborated by abnormal regional cell proliferation patterns observed when fissure invagination is blocked in BMP KO embryos.
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