Levels of retinoic acid and retinaldehyde dehydrogenase expression in eyes of the Mitf-vit mouse model of retinal degeneration.
OBJECTIVE
Several reports have characterized the retinal degeneration observed in the Mitf(vit) mutant mouse. Despite these reports, the factor(s) that may cause or modulate the degeneration still are not well defined; however, it is known that the photoreceptors of Mitf(vit) mice die through an apoptotic mechanism. We reported previously that retinoid metabolism in the RPE of Mitf(vit)++ mice is perturbed. Retinoids regulate genes via the RAR and RXR nuclear receptor pathway that are involved in numerous cellular responses including apoptosis. It is possible that retinoic acid (RA) modulates the retinal degeneration observed in the Mitf(vit) mice. The purpose of this study was to evaluate the levels of RA in whole eyes, as well as its distribution between neural retina and RPE, of the Mitf(vit) mutant mouse model. An additional purpose was to examine the expression of the RA generating enzyme, retinaldehyde dehydrogenase (AHD2), in the eyes of mutant and control mice.


METHODS
The distribution of AHD2 in eyes of pre- and postnatal Mitf(vit) and C57BL/6 wild-type mice was determined immunohistochemically. Quantitative and qualitative analyses of RA were performed using reversed-phase high performance liquid chromatography (HPLC).


RESULTS
The distribution of AHD2 in ocular tissues was similar between pre- and postnatal Mitf(vit) and C57BL/6 control mice. At postnatal week 10, however, a marked increase in AHD2 immunoreactivity was noted in the central dorsal neural retina of Mitf(vit) mice. No differences in the level of total RA in whole eyes were noted between Mitf(vit) and control mice at early postnatal ages. By 10 weeks of age there was a significant elevation of RA that was localized to the neural retina.


CONCLUSIONS
In this study, we show a high level of AHD2 and RA in the neural retina of Mitf(vit) mice relative to control mice. It is possible that this elevation of RAs contributes to the retinal degeneration observed in Mitf(vit) mice either by inducing apoptosis or by enhancing the effect of some other factor(s) involved in the apoptotic pathway.
Duncan
T
T
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Swint
C
C
Smith
S B
SB
Wiggert
B N
BN
D000445:Aldehyde Oxidoreductases / Q000096:biosynthesis*; D000818:Animals; D000831:Animals, Newborn; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005123:Eye / Q000196:embryology / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010857:Pigment Epithelium of Eye / Q000196:embryology / Q000378:metabolism; D012160:Retina / Q000196:embryology / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism*; D050697:Retinal Dehydrogenase; D013997:Time Factors; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; D050697:Retinal Dehydrogenase