Targeted ablation of the Pde6h gene in mice reveals cross-species differences in cone and rod phototransduction protein isoform inventory.
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.
From the Institute of Pharmacy, Department of Pharmacology, Toxicology and Clinical Pharmacy.
Christina
C
Brennenstuhl
Division of Ocular Neurodegeneration.
Naoyuki
N
Tanimoto
From the Institute of Pharmacy, Department of Pharmacology, Toxicology and Clinical Pharmacy.
Markus
M
Burkard
From the Institute of Pharmacy, Department of Pharmacology, Toxicology and Clinical Pharmacy.
Rebecca
R
Wagner
Division of Experimental Ophthalmology, and.
Sylvia
S
Bolz
Division of Experimental Ophthalmology, and.
Dragana
D
Trifunovic
From the Institute of Pharmacy, Department of Pharmacology, Toxicology and Clinical Pharmacy.
Clement
C
Kabagema-Bilan
Division of Experimental Ophthalmology, and.
Francois
F
Paquet-Durand
Division of Ocular Neurodegeneration.
Susanne C
SC
Beck
Division of Ocular Neurodegeneration.
Gesine
G
Huber
Division of Ocular Neurodegeneration.
Mathias W
MW
Seeliger
From the Institute of Pharmacy, Department of Pharmacology, Toxicology and Clinical Pharmacy.
Peter
P
Ruth
the Molecular Genetics Laboratory, Centre for Ophthalmology, University of Tuebingen, 72076 Tuebingen, Germany bernd.wissinger@uni-tuebingen.de.
Bernd
B
Wissinger
From the Institute of Pharmacy, Department of Pharmacology, Toxicology and Clinical Pharmacy, robert.lukowski@uni-tuebingen.de.
Robert
R
Lukowski
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D003117:Color Vision Defects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006152:Cyclic GMP / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics* / Q000378:metabolism; D004596:Electroretinography; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D055537:Light Signal Transduction / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000172:deficiency / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity
D020033:Protein Isoforms; D021122:Protein Subunits; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517444:Pde6g protein, mouse; C000619947:Pde6h protein, mouse; D006152:Cyclic GMP
Cyclic GMP (cGMP); Mouse Genetics; Phosphodiesterases; Retina; Retinal Degeneration; Second Messenger; Vision