Abstract
Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF). Failure of this event leads to congenital vision impairment in the form of coloboma. Recent studies have suggested hyaloid vasculature to be involved in OF fusion. In order to examine this link, we analyzed OF fusion and hyaloid vasculogenesis in the zebrafish pax2a noi mutant line. We first determined that pax2a−/− embryos fail to accumulate F-actin in the OF prior to basement membrane (BM) degradation. Furthermore, using 3D and live imaging we observed reduced OF hyaloid vascularization in pax2a−/− embryos. When examining the connection between pax2a loss of function and hyaloid vasculature, we observed significant reduction of talin1 expression, a regulator of hyaloid vasculature. In addition, cranial VEGF expression was found to be reduced in pax2a−/− embryos. Pharmacological inhibition of VEGF signaling phenocopied the pax2a−/− vasculature, F-actin and BM degradation phenotypes. Lastly, we determined that OF associated hyaloid vasculature is a source of mmp2, mmp14a and mmp14b expression and showed that mmp2 is functionally necessary for degradation of OF BM. Taken together we propose a pax2a driven mechanism that ensures proper and timely hyaloid vasculature invasion of the OF in order to facilitate availability of the BM remodeler mmp2.
Highlights
Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF)
In particular we found that pax2a−/− embryos exhibit a decrease in tln[1], hyaloid vasculature makers as well as VEGFaa, VEGFab and VEGFc expression
We propose a novel pathway for the regulation of OF fusion where pax2a mediates proper timing and abundance of hyaloid vasculature cell recruitment to the OF and subsequent vasculature supplied mmp2-dependent basement membrane (BM) degradation
Summary
Vertebrate retinal development requires timely and precise fusion of the optic fissure (OF). Since the hyaloid vasculature requires an open fissure to complete establishment of its network, it has been proposed that migrating hyaloid vasculature cells may regulate the timing of fissure fusion This mechanism could potentially involve vasculature-mediated activation of the fusion machinery within the retinal rim cells, or direct supply of molecular factors, such as matrix proteases[27]. In support of this hypothesis, recent optic cup transplantation experiments in zebrafish embryos confirm that in the absence of hyaloid vasculature, ectopic retinal OFs fail to initiate fusion[28]. We propose a novel pathway for the regulation of OF fusion where pax2a mediates proper timing and abundance of hyaloid vasculature cell recruitment to the OF and subsequent vasculature supplied mmp2-dependent BM degradation
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