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L. K. Moons, E. Janssens; A Role for MMP-14 in the Development of the Optic Pathway in Zebrafish. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5929.
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© ARVO (1962-2015); The Authors (2016-present)
Matrix metalloproteinases (MMPs) are proteinases that cleave structural elements of the extracellular matrix and many molecules involved in signal transduction. Besides a proven detrimental role in neurological diseases, a beneficial role for MMPs in key physiological and regenerative brain events is emerging, pointing out these proteinases as relevant therapeutic targets in the pathological central nervous system. Importantly, MMPs not only affect migration and survival of neurons, axon guidance, myelination and synaptogenesis, but they also seem to modulate neural stem cell properties and differentiation. Also an involvement of MMPs in the development and regeneration of the optic circuit was sporadically reported. However, the nature and working mechanisms of these MMPs and of their natural inhibitors, tissue inhibitors of metalloproteinases (TIMPs), in retinal patterning and retinotectal pathfinding remain largely unidentified.Methods and
We analysed the spatiotemporal expression pattern of MMP-14 (membrane-type MMP-1) in developing zebrafish embryos by whole mount in situ hybridization and immunohistochemistry and showed this protease to be expressed in the eye and in several regions of the brain, including the optic tectum. Knockdown of MMP14a, using a specific MMP14a morpholino (MO), revealed no abnormalities in gastrulation or early brain development. Interestingly, subsequent immunostainings with the axonal marker anti-acetylated α-tubulin, showed a significant reduction in the size of the optic tectum at 3 and 5 days post fertilization (dpf; p<0.05). MMP14a knockdown also resulted in a disrupted/delayed formation of the retinotectal projections in two transgenic fish lines, Tg(Ath5:GFP) and Tg(Brn3c:GFP), expressing eGFP in their retinal ganglion cells (RGCs). Similar injections with standard MO did not result in any of the observed defects. Morphometric analyses further revealed that MMP14a-MO-injected embryos developed smaller eyes than those of control embryos at 5dpf (p<0.05) whereas the total body length remained unchanged. As preliminary data also showed a reduced number of RGCs in the neuroretina, we are currently looking into some processes possibly contributing to the defective development of the eye and visual system by an in depth analysis of the differentiation and maturation of RGCs, their axonal outgrowth, elongation, navigation and synapse formation in the optic pathway.
These findings reveal a prominent role for MM14a in the development of the neuroretina and the retinotectal pathway in zebrafish. Our results might have implications for future strategies interfering with optic circuit development and/or regeneration.
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