Cell-Type Specific Roles for PTEN in Establishing a Functional Retinal Architecture

Abstract

BackgroundThe retina has a unique three-dimensional architecture, the precise organization of which allows for complete sampling of the visual field. Along the radial or apicobasal axis, retinal neurons and their dendritic and axonal arbors are segregated into layers, while perpendicular to this axis, in the tangential plane, four of the six neuronal types form patterned cellular arrays, or mosaics. Currently, the molecular cues that control retinal cell positioning are not well-understood, especially those that operate in the tangential plane. Here we investigated the role of the PTEN phosphatase in establishing a functional retinal architecture.Methodology/Principal FindingsIn the developing retina, PTEN was localized preferentially to ganglion, amacrine and horizontal cells, whose somata are distributed in mosaic patterns in the tangential plane. Generation of a retina-specific Pten knock-out resulted in retinal ganglion, amacrine and horizontal cell hypertrophy, and expansion of the inner plexiform layer. The spacing of Pten mutant mosaic populations was also aberrant, as were the arborization and fasciculation patterns of their processes, displaying cell type-specific defects in the radial and tangential dimensions. Irregular oscillatory potentials were also observed in Pten mutant electroretinograms, indicative of asynchronous amacrine cell firing. Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals. Finally, while some features of the Pten mutant retina appeared similar to those reported in Dscam-mutant mice, PTEN expression and activity were normal in the absence of Dscam.Conclusions/SignificanceWe conclude that Pten regulates somal positioning and neurite arborization patterns of a subset of retinal cells that form mosaics, likely functioning independently of Dscam, at least during the embryonic period. Our findings thus reveal an unexpected level of cellular specificity for the multi-purpose phosphatase, and identify Pten as an integral component of a novel cell positioning pathway in the retina.

mTor-signaling is required for the formation of proliferating Müller glia-derived progenitor cells in the chick retina

“…By contrast, PI3K/Akt signaling is an important 'hub' in the network of pathways required for the formation of MGPCs in the zebrafish retina (Wan et al, 2014). During development of the mammalian retina, loss of function of PTEN, leading to gains in PI3K/Akt signaling, disrupts the mosaic patterning and dendritic morphogenesis of inner retinal neurons, whereas cell proliferation and cell fate are unaffected (Sakagami et al, 2012;Cantrup et al, 2012). Collectively, these findings indicate context-and speciesspecific functions of PI3K/Akt and mTor signaling in developing and regenerating retina.…”

Brain patterning perturbations following PTEN loss

“…Pax-6-Cre-mediated deletion results in accelerated neurogenesis and premature loss of retinal progenitor cells accompanied by tissue hypertrophy not attributed to excessive stem cell production (Cantrup et al, 2012). This is in contrast to observations from other neuronal progenitor populations (see below) and illustrates the importance of spatio-temporal context in determining the cellular consequence to PTEN loss.…”

Development of Retinal Amacrine Cells and Their Dendritic Stratification

“…Recent studies in Zebrafish have shown the role of transcription factor Irx7 in regulating retinal lamination by affecting neurite outgrowth [38]. Another factor namely PTEN phosphatase also mediates the mosaic spacing, fasciculation, and dendritic arborization of TH amacrine cells and of horizontal cells, likely in a Dscam/Sema-independent manner [39]. Although we currently understand the role of these signaling molecules in IPL development, we are yet to assimilate the full network of molecules upstream and downstream of the signaling factors that play into this regulation.…”