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Ana Ojeda, Peter Y Lwigale; The chemokine CXCL14 regulates neurovascular patterning during cornea development. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6154.
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© ARVO (1962-2015); The Authors (2016-present)
Spatiotemporal signaling events of secreted molecules in the developing anterior eye guide intricate processes that result in the formation of a highly innervated but avascular cornea. Although there is increased interest in chemokines due to their involvement in cell proliferation, migration, and differentiation during embryogenesis, very little is known about their function in the eye. Based on the distinct expression pattern of CXCL14 chemokine in the anterior eye, we hypothesize that CXCL14 plays a role during the development of corneal innervation and avascularity.
Embryonic day (E)1 chick or Tg(tie1: H2B:eYFP) transgenic Japanese quail embryos were injected with RCAS-CXCL14-shRNA or RCAS control, and re-incubated for additional 9-11 days. Embryos were collected and examined for neurovascular defects in cornea development by immunofluorescent staining of whole-mount and corneal sections. The effect of CXCL14 on axon growth and cornea neovascularization was examined in vitro on isolated trigeminal sensory neurons and in vivo by bead implantation in developing cornea, respectively.
Whole-mount analysis of ocular nerves in CXCL14 loss-of-function embryos indicated exacerbated projection of sensory nerves into the cornea. Cross-sections through E12 corneas revealed significantly increased stromal nerve density (P<0.001), stromal nerve occupancy (P<0.001) and innervation of the corneal epithelium (P<0.01) in CXCL14 knockdown embryos compared to controls. In vitro analysis showed that CXCL14 inhibits CXCL12-mediated sensory axon growth. Furthermore, Knockdown of CXCL14 in transgenic quail embryos caused ectopic migration of YFP fluorescently labeled angioblasts into the cornea that resulted in cornea neovascularization, and bead implantation experiments revealed that CXCL14 inhibits VEGF-induced cornea neovascularization.
Collectively, these results demonstrate that CXCL14 plays a crucial role in the precise patterning of corneal innervation and maintenance of avascularity by limiting sensory nerve projection and preventing angioblast migration into the cornea. These findings identify CXCL14 as a novel regulator of the neurovascular patterning in the anterior eye during development.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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