Abstract
BackgroundThe absence or deficiency of melanin as in albinos, has detrimental effects on retinal development that include aberrant axonal projections from eye to brain and impaired vision. In pigmented retinal pigment epithelium (RPE), dihydroxyphenalanine (L-Dopa), an intermediate in the synthetic path for melanin, has been hypothesized to regulate the tempo of neurogenesis. The time course of expression of retinal L-Dopa, whether it is harbored exclusively in the RPE, the extent of deficiency in albinos compared to isogenic controls, and whether L-Dopa can be restored if exogenously delivered to the albino have been unknown.Methodology/Principal FindingsL-Dopa and catecholamines including dopamine extracted from retinas of pigmented (C57BL/6J) and congenic albino (C57BL/6J-tyrc2j) mice, were measured throughout development beginning at E10.5 and at maturity. L-Dopa, but not dopamine nor any other catecholamine, appears in pigmented retina as soon as tyrosinase is expressed in RPE at E10.5. In pigmented retina, L-Dopa content increases throughout pre- and postnatal development until the end of the first postnatal month after which it declines sharply. This time course reflects the onset and completion of retinal development. L-Dopa is absent from embryonic albino retina and is greatly reduced in postnatal albino retina compared to pigmented retina. Dopamine is undetectable in both albino and pigmented retinas until after the postnatal expression of the neuronal enzyme tyrosine hydroxylase. If provided to pregnant albino mothers, L-Dopa accumulates in the RPE of the fetuses.ConclusionsL-Dopa in pigmented RPE is most abundant during development after which content declines. This L-Dopa is not converted to dopamine. L-Dopa is absent or at low levels in albino retina and can be restored to the RPE by administration in utero. These findings further implicate L-Dopa as a factor in the RPE that could influence development, and demonstrate that administration of L-Dopa could be a means to rescue developmental abnormalities characteristic of albinos.
Highlights
The mature neural retina (NR) is a layered sheet of photoreceptors, interneurons, projection neurons and radial glial cells
L-Dopa in pigmented retinal pigment epithelium (RPE) is most abundant during development after which content declines
At the back of the NR is a single layer of pigmented epithelial cells, the retinal pigment epithelium (RPE)
Summary
The mature neural retina (NR) is a layered sheet of photoreceptors, interneurons, projection neurons (retinal ganglion cells) and radial glial cells. At the back of the NR is a single layer of pigmented epithelial cells, the retinal pigment epithelium (RPE). The biogenesis and/or packaging of the melanin pigment in the RPE is defective and, as a consequence, the development of the adjacent NR is flawed. Defects in pigment production are accompanied by faulty development of the NR: there are reports of an initial surplus of mitotic cells [7], a disrupted pace of neurogenesis [8], lack of cells in the fovea, and reduction in the numbers of uncrossed retinal ganglion cell axons to central targets [9,10,11,12]. The absence or deficiency of melanin as in albinos, has detrimental effects on retinal development that include aberrant axonal projections from eye to brain and impaired vision. The time course of expression of retinal L-Dopa, whether it is harbored exclusively in the RPE, the extent of deficiency in albinos compared to isogenic controls, and whether L-Dopa can be restored if exogenously delivered to the albino have been unknown
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