Analysis of Genetically Targeted RanBP2 Mice in Glucose Metabolism and Retinal Function

Abstract

Abstract: : Purpose: The Ran–binding protein 2 (RanBP2) is a large mosaic protein unique to vertebrates. Recent efforts have identified a diverse set of molecular partners, each interacting specifically with selective domains of RanBP2. Moreover, RanBP2 has been implicated in multiple cellular functions such as nucleocytoplasmic trafficking, protein biogenesis, formation of the mitotic spindle and assembly of the nuclear envelope. However, the implication(s) of any of these cellular functions of RanBP2 in physiological processes and retinal physiology are not understood. The focus of this study was to determine the function of RanBP2 in animal and retinal physiology. Methods: We generated a mouse model harboring the disruption of the RanBP2 locus. Mice were analyzed under different genetic backgrounds by multidisciplinary approaches. Results: Analysis of the Mendelian ratios of the offspring produced from RanBP2^+/– x RanBP2^+/– crosses supports that RanBP2^–/– mice are early embryonic lethal. The RanBP2 locus was also happloinsufficient. RanBP2^+/– mice exhibited a number of physiological phenotypes and some of which were dependent on the sex, age and genetic background. Congenic 129ola RanBP2^+/– male > 6 months old, but neither 3–4 months old nor female mice and nor male mice with a mixed 129ola/C57Bl6 genetic background, exhibited significant deficits in glucose metabolism upon glucose challenge and when placed on a high fat diet. In contrast, RanBP2^+/– female but not male mice with a mixed 129ola/C57Bl6 background and on low and high fat diet exhibited increased but significantly different glycogen levels in the liver. Old RanBP2^+/– male (9–12 months) but not age–matched female mice had decreased body weight and similar levels of food consumption. RanBP2^+/– male mice had ERG deficits. These were manifested as a reduction of the scotopic b–wave and a trend towards a reduced photopic b–wave and scotopic a–wave. Finally, there was no difference in the average of the density of nuclear pores (NPC) at the nuclear envelope (∼ 3–4 NPC/µm²) between wild type and heterozygous RanBP2 litters (P0). Conclusions: Mild reductions in RanBP2 levels uncovered a diverse set of physiological pertubrations supporting a determinant function of RanBP2 and genetic modifiers of this in modulating glucose metabolism. These data support that the RanBP2 mouse model may serve as a disease model to complex disorders such as diabetes type II and allied retinal disorders such as diabetic retinopathies.

Keywords: genetics • metabolism • diabetes