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Peter G Fuerst, Shuai Li, Ivy S Samuels, Aaron Simmons; DSCAM restricts neurite lamination in the mouse inner retina. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1477.
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© ARVO (1962-2015); The Authors (2016-present)
During development of the retina an overproduction of cells occurs. Neurons initially project neurites into a broad area of the retinal plexiform layers that is refined during development, as the cells form synapses with the appropriate cell types. This process is required in order for the cells to survive and involves feedback provided by molecules such as neurotrophins and other growth factors. While this process is beginning to be understood, how cells that make functional but inappropriate contacts are remodeled, refined or eliminated remains a largely open question.
We address the question of neurite refinement in the mouse retina, in which a large number of cell adhesion molecules directs cells to the appropriate lamina and facilitate the highly organized connectivity observed in this tissue. Using loss and gain of function models of the Down syndrome cell adhesion molecule (Dscam) and loss of function models of Bax we test the roles of cell death and cell adhesion and avoidance in the refinement of retinal neurites.
We find that DSCAM and Bax can independently promote cell death in the inner retina during refinement, but that most developmental cell death in the retina is triggered through DSCAM mediated interactions that are executed through Bax dependent pathways. Utilizing loss and gain of function mouse models of Dscam to assay refinement of antibody and genetically labeled neurons during development, we find that mouse Dscam does not actively promote avoidance of neurites, but rather acts to limit the lamina in which exploring neurites are able to remain within. By conditionally generating mosaic retinas, we also find that cells with improperly refined neurites are able to induce improper synaptic organization in neighboring wild type cells, relevant to cell based therapies in which wild type cells must integrate into a damaged retina in which extensive synaptic remodeling has occurred.
Based on these studies we propose a model to account for the numerous Dscam loss and gain of function phenotypes reported in the retina. In this model DSCAM functions to weaken connectivity mediated by overlapping expression of adhesion molecules to eliminate inappropriately placed cells and connections and thereby promote refinement of retinal neurites.
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