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Expression of exogenous PDE5 rescues photoreceptors in rd1 mice.

BACKGROUND
Catalytic hydrolysis of cyclic guanosine monophosphate (cGMP) by phosphodiesterase 6 (PDE6) is a critical step in phototransduction signalling in photoreceptors. Mutations in the genes encoding any of the three PDE6 subunits are associated with retinitis pigmentosa, the most common form of inherited retinal diseases. The rd1 mouse carries a naturally occurring nonsense mutation in the Pde6b gene. The rd1 mouse retina rapidly degenerates and fails to form rod photoreceptor outer segments due to the elevated cGMP level and subsequent excessive Ca2+ influx. In this study, we aim to test whether the expression of PDE5, a non-photoreceptor-specific member of the PDE superfamily, rescues photoreceptors in the rd1 retina.


METHODS
The PDE5 expression plasmid was used to transfect neonatal rd1 mice by electroporation. The degeneration of the mouse retina was assessed by staining of retinal sections with DAPI. The expression and localization of phototransduction proteins in photoreceptors was analyzed by immunostaining. The expression of proteins in cultured cells was analyzed by immunoblotting.


RESULTS
The expression of exogenous PDE5, a non-photoreceptor-specific member of the PDE superfamily, prevents photoreceptor degeneration in rd1 mice. Unlike endogenous photoreceptor-specific PDE6 that was localised in the outer segments of photoreceptors, ectopically-expressed PDE5 was distributed in inner segments and synaptic terminals. PDE5 also promoted the development of the outer segments in rd1 mice. Co-expression of PDE5 and rhodopsin in cultured cells showed enhanced rhodopsin expression.


CONCLUSION
Lowering the cGMP level in photoreceptor by PDE5 is sufficient to rescue photoreceptors in rd1 retinas. cGMP may also be involved in the regulation of rhodopsin expression in photoreceptors.