Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia
Tanya Tolmachova, … , Clare Huxley, Miguel C. Seabra
Tanya Tolmachova, … , Clare Huxley, Miguel C. Seabra
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):386-394. https://doi.org/10.1172/JCI26617.
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Research Article Ophthalmology

Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia

Abstract

Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium (RPE), photoreceptors, and choroid, caused by loss of function of the CHM/REP1 gene. REP1 is involved in lipid modification (prenylation) of Rab GTPases, key regulators of intracellular vesicular transport and organelle dynamics. To study the pathogenesis of CHM and to develop a model for assessing gene therapy, we have created a conditional mouse knockout of the Chm gene. Heterozygous-null females exhibit characteristic hallmarks of CHM: progressive degeneration of the photoreceptors, patchy depigmentation of the RPE, and Rab prenylation defects. Using tamoxifen-inducible and tissue-specific Cre expression in combination with floxed Chm alleles, we show that CHM pathogenesis involves independently triggered degeneration of photoreceptors and the RPE, associated with different subsets of defective Rabs.

Authors

Tanya Tolmachova, Ross Anders, Magnus Abrink, Laurence Bugeon, Margaret J. Dallman, Clare E. Futter, José S. Ramalho, Felix Tonagel, Naoyuki Tanimoto, Mathias W. Seeliger, Clare Huxley, Miguel C. Seabra

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Figure 4

Histological analysis of sections of eyes of Chm mutant mice.

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Histological analysis of sections of eyes of Chm mutant mice. ...
(A–H) Chmnull/WT mice at 2 (A), 4 (B), 8 (C and F–H), and 16 (D) months, and ChmWT/WT mice at 10 months (E). (I and J) Detection of Cre protein (red) in TM-induced (+TM) (I) and non–TM-induced (J) mice carrying the MerCreMer transgene (MCM) with a Cre-specific antibody. (K and L) Histological analysis of TM-induced (+TM) (K) and non–TM-induced (L) Chm3lox/Y mice carrying the MerCreMer transgene (MCM) at 9–10 months. Analysis was carried out 8 months after TM injection (8 mpi). (M–P) Two-month-old ChmWT/Y (M) and Chmflox/Y (N) mice, and Chmflox/Y six3-Cre+ mice at 2 (O) and 4 (P) months. CH, choroid; RPE, retinal pigment epithelium; OS, photoreceptor outer segments; ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. Scale bars: 20 μm. Magnification, ×230 (A, inset), ×450 (K, inset).