BETA2/NeuroD1 null mice: a new model for transcription factor-dependent photoreceptor degeneration.
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.
Pennesi
Mark E
ME
Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cho
Jang-Hyeon
JH
Yang
Zhuo
Z
Wu
Schonmei H
SH
Zhang
Jian
J
Wu
Samuel M
SM
Tsai
Ming-Jer
MJ
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004596:Electroretinography; D017930:Genes, Reporter; D006720:Homozygote; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D012160:Retina / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000473:pathology; D012374:Rod Cell Outer Segment / Q000648:ultrastructure; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C501008:Neurod1 protein, mouse