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Indulekha Chandrasekharan Pillai Lalitha, Nomingerel Tserentsoodol, Kyoung-in Cho, Paulo A. Ferreira; Probing The Role(s) Of The Loss Of RAN-Binding Protein-2 (RANBP2) In M-cone Photoreceptors And Sub-Populations Of Brain Neurons. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1816.
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The RANBP2 is a pleiotropic protein, which assembles a large and dynamic protein complex and whose components are implicated in mediating inter-dependent biological processes in a cell context- or stress-dependent manner. In particular, RANBP2 is known to regulate nucleocytoplasmic trafficking, oxidative stress signaling, proteostasis and lipid homeostasis, and mitochondria function and dynamics. For example, semi-dominant mutations in RANBP2 in the human and haploinsuficiency of RANBP2 in the mouse modulate distinctively the susceptibility of neurons to death against various stressors. The goal of this work is to assess the cell-context dependent role of RANBP2 and its accessory partners between M-cone photoreceptors and subpopulations of neurons in the brain.
We used a conditional gene targeting approach to knock-out selectively RANBP2 either in M-cone photoreceptors or Thy1+- andYFP-labeled dentate gyrus (DG) and some other brain neurons (e.g. CA3). Mice with loxP-RANBP2 and expressing the Cre recombinase under control of either the human L/M opsin or tamoxifen-inducible Thy1 promoters were analyzed by immunohistochemistry and light microscopy, and morphologically, with antibodies against various protein markers.
Retinal flat mounts and cross sections revealed that loss of RANBP2 selectively in M-cone photoreceptors causes the rapid loss of M-cones with very few (~3-5%) remaining in 6-8 week-old RANBP2-/- mice. Some of the surviving M-cones appear to retain well developed outer segments and without apparent gross mislocalization of M-opsin in the inner segment. Likewise, apparent differences in cone arrestin distribution were not found between wild-type and RANBP2-/- mice. However, loss of RANBP2 leads first to the degeneration of the outer and inner segments without apparent changes to cell bodies, inner fibers and pedicles of cone photoreceptors. Conversely, DG and CA3 neurons with loss of RANBP2 remain viable without apparent neuronal cell loss and changes in gross morphological features. Yet, mice with loxP-RANBP2-/-,Thy1-cre become lethargic and die within 6 days of the last tamoxifen administration dose.
These results underscore further distinct roles of the RANBP2 assembly complex among neuronal cell types that reflect the cell type-dependent regulation of a defined but functionally diverse set of accessory proteins by RANBP2.
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