Targeted Ablation of the Pde6h Gene in Mice Reveals Cross-species Differences in Cone and Rod Phototransduction Protein Isoform Inventory

• Published in: The Journal of biological chemistry Vol. 290; no. 16; pp. 10242 - 10255
• Main Authors: Brennenstuhl, Christina, Tanimoto, Naoyuki, Burkard, Markus, Wagner, Rebecca, Bolz, Sylvia, Trifunovic, Dragana, Kabagema-Bilan, Clement, Paquet-Durand, Francois, Beck, Susanne C., Huber, Gesine, Seeliger, Mathias W., Ruth, Peter, Wissinger, Bernd, Lukowski, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.04.2015; American Society for Biochemistry and Molecular Biology
• Subjects: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Color Vision Defects - genetics; Color Vision Defects - metabolism; Color Vision Defects - pathology; Cyclic GMP (cGMP); Cyclic GMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 6 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism; Electroretinography; Gene Deletion; Gene Expression; Humans; Light Signal Transduction - genetics; Mice; Mice, Knockout; Mouse Genetics; Phosphodiesterases; Protein Isoforms - deficiency; Protein Isoforms - genetics; Protein Subunits - genetics; Protein Subunits - metabolism; Retina; Retinal Cone Photoreceptor Cells - cytology; Retinal Cone Photoreceptor Cells - metabolism; Retinal Degeneration; Retinal Rod Photoreceptor Cells - cytology; Retinal Rod Photoreceptor Cells - metabolism; Second Messenger; Signal Transduction; Species Specificity; Vision; Retinal Degeneration; Second Messenger; Vision; Mouse Genetics; Retina; Phosphodiesterases; Cyclic GMP (cGMP)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.611921

Phosphodiesterase-6 (PDE6) is a multisubunit enzyme that plays a key role in the visual transduction cascade in rod and cone photoreceptors. Each type of photoreceptor utilizes discrete catalytic and inhibitory PDE6 subunits to fulfill its physiological tasks, i.e. the degradation of cyclic guanosine-3′,5′-monophosphate at specifically tuned rates and kinetics. Recently, the human PDE6H gene was identified as a novel locus for autosomal recessive (incomplete) color blindness. However, the three different classes of cones were not affected to the same extent. Short wave cone function was more preserved than middle and long wave cone function indicating that some basic regulation of the PDE6 multisubunit enzyme was maintained albeit by a unknown mechanism. To study normal and disease-related functions of cone Pde6h in vivo, we generated Pde6h knock-out (Pde6h−/−) mice. Expression of PDE6H in murine eyes was restricted to both outer segments and synaptic terminals of short and long/middle cone photoreceptors, whereas Pde6h−/− retinae remained PDE6H-negative. Combined in vivo assessment of retinal morphology with histomorphological analyses revealed a normal overall integrity of the retinal organization and an unaltered distribution of the different cone photoreceptor subtypes upon Pde6h ablation. In contrast to human patients, our electroretinographic examinations of Pde6h−/− mice suggest no defects in cone/rod-driven retinal signaling and therefore preserved visual functions. To this end, we were able to demonstrate the presence of rod PDE6G in cones indicating functional substitution of PDE6. The disparities between human and murine phenotypes caused by mutant Pde6h/PDE6H suggest species-to-species differences in the vulnerability of biochemical and neurosensory pathways of the visual signal transduction system. Background: Phosphodiesterase-6 (PDE6) is a multisubunit enzyme essential for visual signal processing. Rare mutations in the human PDE6H gene result in incomplete color blindness. Results:Pde6h-deficient mice exhibit no signs of photoreceptor dysfunction. Conclusion: PDE6 configurations differ between species and are more interchangeable than previously thought. Significance: Presence of related isoforms in the retina may allow adjustments of the phototransduction components thereby preventing the occurrence of pathological conditions.