Unlike VLDLR, the role of ApoER2 in the retina has not been investigated in detail. The basic function of VLDLR in the retina has been difficult to determine, as mice deficient in VLDLR develop pervasive choroidal neovascularization and subsequent retinal degeneration at a young age ( Heckenlively et al., 2003 Li et al., 2007 Hu et al., 2008). The relationship between apoE alleles and retinal pathology underscores the importance of understanding the function of apoE receptors in the normal and diseased retina. These events are also observed in VLDLR KO mice without dietary modifications ( Hu et al., 2008), which suggests that diet and apoE genotype may directly impact the signaling integrity of VLDLR and other lipoprotein receptors. Mice expressing human apoE alleles and fed high-fat, high-cholesterol diets demonstrate differential susceptibility to AMD-like characteristics, such as neovascularization and retinal degeneration ( Malek et al., 2005). Similar to Reelin, ApoE acts via lipoprotein receptors to modulate a variety of physiological processes. ApoE plays an essential role in serum cholesterol homeostasis by mediating transport of lipids and cholesterol into cells ( Kesaniemi et al., 1987). In light of the cell-specific expression of Reelin and Dab1 in the retina and the mild retinal phenotype in mutant mice, the retina may provide an ideal model for further genetic dissection of the Reelin signaling pathway and exploration of mechanisms important for the development and maintenance of retinal circuitry.ДЄge-related macular degeneration (AMD) is a late-onset, multifactorial neurodegenerative disease of the retina, which shares numerous risk factors with Alzheimer's disease, particularly association with certain Apoe alleles (encoding apolipoprotein E, apoE) ( Baird et al., 2004 Malek et al., 2005 Baird et al., 2006). In the developing and adult retinas, Dab1 expression is mostly restricted to A-II amacrine cells, while Reelin is expressed by some amacrine cells, cone bipolar cells, and retinal ganglion cells ( Rice et al., 2001). While Dab1 and Reelin mutant mice do not have alterations in neuronal positioning in the retina, they do have abnormal rod bipolar cell morphology and survival, A-II amacrine synapse structure, and synaptic connectivity ( Rice et al., 2001). Mice carrying null mutations in Reln and Dab1 have impaired neuronal migration during development resulting in severe brain lamination defects ( D'Arcangelo et al., 1995 Sheldon et al., 1997). Reelin signaling through these receptors is required for a range of processes in the developing and adult brain, including neuronal migration ( Hiesberger et al., 1999 Andrade et al., 2007), dendritic development ( Niu et al., 2004), and synaptic plasticity ( Weeber et al., 2002 Beffert et al., 2005 Beffert et al., 2006b). Following ligand binding, the adaptor protein Disabled-1 (Dab1) associates with receptor C-terminal NPxY motifs, is tyrosine phosphorylated by members of the Src-family kinases, and transduces the Reelin signal downstream ( Benhayon et al., 2003). Reelin is a large secreted glycoprotein that binds to the lipoprotein receptors apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR) ( Hiesberger et al., 1999). These results support a pivotal role for ApoER2 in the establishment and maintenance of normal retinal synaptic connectivity. Interestingly, age-related reductions in rod and cone function were observed in both ApoER2 and VLDLR KOs. VLDLR KO mice also had reductions in oscillatory potentials and delayed synaptic response intervals. Mice deficient in another Reelin receptor, very low-density lipoprotein receptor (VLDLR), had normal rod bipolar morphology but altered A-II amacrine dendritic development. The presence of an intact ApoER2 NPxY motif, necessary for binding Disabled-1 and transducing the Reelin signal, was also necessary for development of the rod bipolar pathway, while the alternatively spliced exon 19 was not. ApoER2 knock-out (KO) mice had rod bipolar morphogenic defects, altered A-II amacrine dendritic development, and impaired rod-driven retinal responses. Both during development and in the adult, ApoER2 was expressed by A-II amacrine cells. ApoER2 expression was highest during postnatal inner retinal synaptic development and was considerably lower in the mature retina. Here we describe the function of ApoER2 in the developing and adult retina. Reelin and apolipoprotein E (apoE), ligands of apoE receptor 2 (ApoER2), are involved in retinal development and degeneration, respectively. The cellular and molecular mechanisms responsible for the development of inner retinal circuitry are poorly understood.

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