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The Journal of Neuroscience, January 15, 2003, 23(2):453-461
BETA2/NeuroD1 Null Mice: A New Model for Transcription Factor-Dependent Photoreceptor Degeneration
Mark E. Pennesi1, 2, *, Jang-Hyeon Cho3, *, Zhuo Yang1, Schonmei H. Wu1, Jian Zhang1, Samuel M. Wu1, 2, and Ming-Jer Tsai3, 4 1 Department of Ophthalmology, 2 Division of Neuroscience, 3 Department of Molecular and Cellular Biology, and 4 Program of Developmental Biology, Baylor College of Medicine, Houston, Texas 77030
BETA2/NeuroD1 is a basic helix-loop-helix transcription factor that is expressed widely throughout the developing nervous system. Previous studies have shown that BETA2/NeuroD1 influences the fate of retinal cells in culture. To analyze the effect of BETA2/NeuroD1 on the structure and function of the retina, we examined a line of BETA2/NeuroD1 knock-out mice that survives until adulthood. At 2-3 months of age, homozygous null mice showed a 50% reduction in rod-driven electroretinograms (ERGs) and a 65% reduction in cone-driven ERGs. ERGs measured from knock-out mice that were >9 months of age were undetectable. At 2-3 months, the number of photoreceptors in the outer nuclear layer was reduced by 50%. In addition, electron microscopy showed that the surviving photoreceptors had shortened outer segments. The number of cones labeled by peanut agglutinin was decreased 50-60%. By 18 months, retinas from null mice were completely devoid of photoreceptors. There appeared to be few changes in the inner retina, although BETA2/NeuroD1 is expressed in this area. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining revealed a dramatic increase in cell death, peaking at approximately postnatal day 3 and continuing into adulthood. No defects in cell birth were detected using bromodeoxyuridine staining. Our results reveal that BETA2/NeuroD1 not only plays an important role in terminal differentiation of photoreceptors but also serves as a potential survival factor. Loss of BETA2/NeuroD1 results in an age-related degeneration of both rods and cones.
Key words: retina; BETA2/NeuroD1; BETA2; NeuroD; NeuroD1; photoreceptor; degeneration; development; bHLH; electroretinogram; differentiation
* M.E.P. and J.-H.C. contributed equally to this work.
Copyright © 2003 Society for Neuroscience 0270-6474/03/232453-09$05.00/0
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