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Didier Hodzic, David Razafsky; Nuclear dynamics in retinal development and homeostasis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5157. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal development, which proceeds through the transformation of a single layer of retinal progenitor cells (RPCs) into three distinct layers of interconnected post-mitotic neurons, involves different types of nuclear movements: 1) interkinetic nuclear migration that consists of nuclear oscillations in phase with the cell cycle within RPCs, 2) the active translocation of nuclei within post-mitotic neurons migrating from their birthplace towards their respective laminar positions, 3) the precise spatial positioning of nuclei from fully differentiated retinal neurons within adult retinas. Linkers of the Nucleoskeleton to the Cytoskeleton (LINC complexes) designate macromolecular complexes that span the nuclear envelope and physically connect the nuclear interior to cytoskeletal networks and molecular motors. LINC complexes assemble within the perinuclear space through direct interactions between the SUN domain of inner nuclear membrane Sun proteins (Sun 1 and Sun 2) and the KASH domain of outer nuclear membrane Nesprins (Nesprin 1, 2, 3 and 4). We previously showed that LINC complexes mediate the positioning cone nuclei in mouse retina using a dominant-negative transgenic approach that consist of the inducible expression of EGFP-KASH, a potent inhibitor of LINC complex assembly.
Here, we developed and characterized a more robust and ubiquitous conditional transgenic mouse model of LINC complex disruption. We also present the developmental expression pattern of LINC complex components during retinal development using immunofluorescence microscopy, semi-quantitative RT-PCR as well as In Situ Hybridization.
Our new mouse model maximizes the mislocalization of cone nuclei (>95%) within the outer plexiform layer. Whereas this mislocalization does not affect the structural organization of inner and outer segments in 6 month-old cones, the structural organization of cone pedicles is drastically affected. This mouse model also allows for the robust and ubiquitous expression of EGFP-KASH within cycling RPCs and post-mitotic RGC. Developmental expression pattern studies of Sun proteins and Nesprins reveal the variability of LINC complexes composition across cell types and developmental stages.
This new mouse model will provide key information related to the involvement of LINC complexes in nuclear dynamics in vivo and to the physiological relevance of nuclear movements during retinal development and homeostasis.
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