Regional abnormalities in retinal development are associated with local ocular hypopigmentation

Abstract

The retinal pigment epithelium (RPE) plays a key role in regulating retinal development. The critical enzyme in pigment production is tyrosinase. Transgenic mice with a tyrosinase construct where the locus control region was deleted (YRT4) display a variegated phenotype of tyrosinase expression. Their central retina is largely pigment free, whereas more peripheral regions are heavily pigmented. We have used this model to ask whether the influence of pigmented RPE over the retina during development is fundamentally governed by local interactions or is global. Our data show that YRT4 eyes have intermediate melanin content and relatively low tyrosinase activity compared with wild-type and albino animals. Rod counts are comparable to those in pigmented mice in peripheral regions but similar to those in albinos centrally. Anterograde labelling of retinal pathways demonstrates the presence of relatively normal ipsilateral chiasmatic projection in YRT4 mice, comparable with that in pigmented animals and consistent with the peripheral pigmented origin of this pathway. Examination of cellular proliferation levels during retinal development reveals that YRT4 mice display an extended period of mitosis, similar to that found in albinos. Hence, our results show that the regulatory influence of the RPE over the developing retina depends on localized interactions between these tissues.

The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells

“…This phenotype is associated with mutations in melanin production or melanosome biogenesis and turnover, and leads to decussation defects and mistargeting (Rice et al, 1995, Herrera et al, 2003, Rebsam et al, 2012, Bhansali et al, 2014, Jeffery, 2001). Birthdating experiments have suggested that this is due to a delay in the generation of RGCs in albino compared with pigmented retina (Bhansali et al, 2014, Drager, 1985, Gimenez et al, 2005, Lavado et al, 2006, Rachel et al, 2002). Given our results suggesting that a number of peripheral RGCs, including 22% of iRGCs, are generated in the CMZ and that their generation depends on Cyclin D2, we asked whether Cyclin D2 expression is compromised in the albino and therefore linked to the reduction of iRGCs.…”

Ectopic expression of tyrosine hydroxylase in the pigmented epithelium rescues the retinal abnormalities and visual function common in albinos in the absence of melanin

“…The section containing the optic nerve head was identified and the sections retained directly above and below were used. Five individuals and both eyes were used per group resulting in n = 20 measurements, as described (Gimenez et al . 2005).…”

“…Outer segments counts were undertaken on 1–2 mm Historesin sections in each of the groups as described (Jeffery et al . 1997; Gimenez et al . 2005).…”

Patterns of cell proliferation and rod photoreceptor differentiation in shark retinas

“…The highly specialised RPE plays a key role in regulating retinal development (Raymond and Jackson, 1995;Martínez-Morales et al, 2004;Gimé nez et al, 2005). Moreover, RPE-derived cells display several properties of neural progenitor cells: (i) neural progenitor identity, based on the expression of markers used to identify neural stem and progenitor cells; (ii) proliferation with limited self-renewal; (iii) and differentiation into neuronal and glial cells based on the expression of differentiation markers (Reh and Levine, 1998;Seaberg and van der Kooy, 2003).…”