Abstract
Purpose :
Dopaminergic amacrine cells (DACs) synthesize dopamine in the retina and influence light adaptation, photoreceptor coupling, and the retinal clock modulation. These neurons develop embryonically and undergo synaptic refinement during the first postnatal week. However, little is known about the drivers of DAC differentiation and lamination.
Methods :
We tested the potential role of the serine/threonine kinase LKB1 as a regulator of DAC development using retina-specific Cre drivers. With littermate controls, we compared the number and lamination of dopaminergic amacrine cells at neonatal time points. We visualized changes in synaptic organization and cell number of DACs and non-dopaminergic amacrine cell subtypes using cell-specific antibodies in retinal cross-sections and whole mounts. Additionally, we characterized associated vasculature defects within the retina.
Results :
LKB1 loss leads to a doubling of DACs and simultaneous ectopic neurite stratification towards the outer layers of the retina, resulting in DAC neurites positioned within the photoreceptor layer. In parallel, we observed that LKB1-deficient DAC doubled in number, which persisted in adulthood. In contrast, the numbers and laminations of other amacrine cell subtypes (cholinergic and GABA-ergic subtypes) were not changed. Retinal vasculature changes accompanied alterations in DAC, resulting in dramatic rearrangement to the vascular layers and reduced vascular complexity.
Conclusions :
Our results indicate that the crucial metabolic regulator, LKB1, is involved in cellular development and specifically required for laminar specificity of DAC. Since the phenotypes persist through adulthood, we hypothesize that LKB1 plays a role in both development and maintenance of dopaminergic amacrine cells, by governing the interplay between vasculature formation and DAC maturation.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.