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Lieve K. Moons, Greet Bervoets, Els Janssens; The Matrix Metalloproteinases Mmp-2 and Mmp-14 Are Involved in Eye and Visual System Development in Zebrafish. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4105.
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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. 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. Although MMPs have been found in virtually every tissue of the eye and their involvement in development and regeneration of the optic circuit was sporadically reported, the nature and working mechanisms of these MMPs in retinal patterning and retinotectal pathfinding remain largely unidentified.
In situ hybridization and immunohistochemistry revealed expression of Mmp-2 and Mmp-14 in developing zebrafish in the eye and in several regions of the brain, including the optic tectum (OT). More specifically in the eye, Mmp-2 expression is found in the inner plexiform layer (IPL) and in the cell bodies, glial fibers and end feet of Müller cells, whereas Mmp-14a is expressed in the IPL and in the nerve fiber layer of the retinal ganglion cells (RGCs). Knockdown of mmp-14a using 2 specific mmp-14a morpholinos (MO) did not show any gastrulation defects, brain developmental abnormalities or differences in body length, but resulted in a significantly reduced size of the eye and OT, as compared to control embryos at different hours post fertilization. BrdU pulse experiments revealed a delay in neural progenitor cell proliferation. Also differentiation of RGCs and amacrine cells as well as retinal lamination was retarded after mmp-14a knockdown. The processes and mechanisms underlying these developmental defects are currently being investigated. Interestingly, similar analyses using specific mmp-14b MO knockdown did not result in any abnormal phenotype. Specific translation knockdown of mmp-2 is being performed to investigate the potential co-involvement of Mmp-2, a physiological substrate of Mmp-14.
Altogether, these novel findings argue for a major role of Mmp-14a, but not Mmp-14b, in the development of the neuroretina and retinotectal pathways in zebrafish.
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