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D.M. Sherry, H. Li, R. Mitchell, D.R. Graham, J.D. Ash; Overexpression of Leukemia Inhibitory Factor (LIF) Disrupts Retinal Development. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5336.
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Purpose: Leukemia Inhibitory Factor (LIF) is a member of a family of cytokines that signal via gp130–coupled receptors, including CNTF, interleukin–6, and oncostatin M. We have shown that LIF can arrest photoreceptor differentiation before determination of rod or cones. In the current study, we sought to analyze the effects of LIF on the morphological differentiation of photoreceptors and other retinal neurons including bipolar cells, horizontal cells, amacrine cells and ganglion cells and their organization within the retina. Methods: Retinal organization and the morphological differentiation of retinal neurons was assessed immunocytochemically using cell–specific markers at postnatal day 14 (eye opening) in transgenic mice that constitutively overexpress LIF. Results: Overexpression of LIF disrupted retinal layering, organization of synaptic layers, and morphological differentiation of several retinal cell types. Patches of retina showed abnormal layering, while adjacent areas showed the usual nuclear and plexiform layers, although organization within the layers was abnormal. The ONL was greatly reduced. Most putative photoreceptors were relatively undifferentiated and there was little evidence of outer segment development. Some putative cone cells were identified by recoverin labeling but showed little outer segment development and often projected into the inner retina. Many photoreceptor terminals were present in the OPL, but the layer was abnormally broad and the arrangement of terminals was highly disrupted. In addition, ectopic ribbon synaptic terminals invaded the INL. Differentiated ON–cone, OFF–cone and rod bipolar cells all were reduced in number and showed abnormal morphology, soma placement, and termination pattern. Large clusters of ribbon synaptic terminals were present in the mid–IPL. In addition, ribbon synaptic terminals often invaded the GCL. Marker labeling indicated that differentiation of several amacrine cell types also was affected, including starburst, AII and VGLUT3 amacrine cells. No labeling for ganglion cell markers was observed, even in regions with a well–developed GCL. Conclusions:LIF inhibits proper development of several retinal cell types including rod, cone, bipolar, amacrine and ganglion cells. Overexpression of LIF also disrupts development of retinal layering, neuronal migration, and synaptic organization. LIF, and other cytokines that signal via gp130–coupled receptors, may regulate many aspects of retinal development.
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