Ectopic expression of tyrosine hydroxylase in the pigmented epithelium rescues the retinal abnormalities and visual function common in albinos in the absence of melanin.
Albino mammals have profound retinal abnormalities, including photoreceptor deficits and misrouted hemispheric pathways into the brain, demonstrating that melanin or its precursors are required for normal retinal development. Tyrosinase, the primary enzyme in melanin synthesis commonly mutated in albinism, oxidizes l-tyrosine to l-dopaquinone using l-3,4-dihydroxyphenylalanine (L-DOPA) as an intermediate product. L-DOPA is known to signal cell cycle exit during retinal development and plays an important role in the regulation of retinal development. Here, we have mimicked L-DOPA production by ectopically expressing tyrosine hydroxylase in mouse albino retinal pigment epithelium cells. Tyrosine hydroxylase can only oxidize l-tyrosine to L-DOPA without further progression towards melanin. The resulting transgenic animals remain phenotypically albino, but their visual abnormalities are corrected, with normal photoreceptor numbers and hemispheric pathways and improved visual function, assessed by an increase of spatial acuity. Our results demonstrate definitively that only early melanin precursors, L-DOPA or its metabolic derivatives, are vital in the appropriate development of mammalian retinae. They further highlight the value of substituting independent but biochemically related enzymes to overcome developmental abnormalities.
Lavado
Alfonso
A
Centro Nacional de Biotecnología (CNB-CSIC), Department of Molecular and Cellular Biology, Campus de Cantoblanco, Madrid, Spain.
Jeffery
Glen
G
Tovar
Victoria
V
de la Villa
Pedro
P
Montoliu
Lluís
L
D000417:Albinism / Q000201:enzymology*; D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006801:Humans; D008543:Melanins / Q000172:deficiency*; D051379:Mice; D050506:Mutant Chimeric Proteins / Q000378:metabolism; D016716:PC12 Cells; D010673:Pheochromocytoma; D010857:Pigment Epithelium of Eye / Q000201:enzymology / Q000473:pathology; D051381:Rats; D012160:Retina / Q000002:abnormalities* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012374:Rod Cell Outer Segment / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism; D014785:Vision, Ocular / Q000502:physiology*
D008543:Melanins; D050506:Mutant Chimeric Proteins; D014446:Tyrosine 3-Monooxygenase