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Cell-type specific roles for PTEN in establishing a functional retinal architecture.

Cantrup R, Dixit R, Palmesino E, Bonfield S, Shaker T, Tachibana N, Zinyk D, Dalesman S, Yamakawa K, Stell WK, Wong RO, Reese BE, Kania A, Sauvé Y, Schuurmans C - PLoS ONE (2012)

Bottom Line: Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals.We 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.

ABSTRACT

Background: The 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 findings: In 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/significance: We 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.

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Abnormal retinal architecture and increased retinal cell sizes in Pten cKOs.(A–D) Low (A,B) and high (C,D) magnification images of hematoxylin-eosin (H&E) stained sections of adult wild-type (A,C) and Pten cKO (B,D) retinae. (E–G) Calbindin labelling of P7 wild-type and Pten cKO retinal sections (E,F) and area measurements of calbindin+ horizontal cells (G). (H–S) Labeling of retinal flatmounts from P21 wild-type and Pten cKOs with calbindin (H,I), ChAT (K,L), TH (N,O), and SMI32 (Q,R). Calculation of cell areas for P21 calbindin+ horizontal cells (J), ChAT+ (M) and calbindin+ (P) amacrine cells and SMI32+ RGCs (S). p values are denoted as follows: <0.05 *, <0.01 **, <0.005 ***. Scale bars = 100 µm (A,B,N,O), 50 µm (C–L,Q,R).
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pone-0032795-g002: Abnormal retinal architecture and increased retinal cell sizes in Pten cKOs.(A–D) Low (A,B) and high (C,D) magnification images of hematoxylin-eosin (H&E) stained sections of adult wild-type (A,C) and Pten cKO (B,D) retinae. (E–G) Calbindin labelling of P7 wild-type and Pten cKO retinal sections (E,F) and area measurements of calbindin+ horizontal cells (G). (H–S) Labeling of retinal flatmounts from P21 wild-type and Pten cKOs with calbindin (H,I), ChAT (K,L), TH (N,O), and SMI32 (Q,R). Calculation of cell areas for P21 calbindin+ horizontal cells (J), ChAT+ (M) and calbindin+ (P) amacrine cells and SMI32+ RGCs (S). p values are denoted as follows: <0.05 *, <0.01 **, <0.005 ***. Scale bars = 100 µm (A,B,N,O), 50 µm (C–L,Q,R).

Mentions: To determine whether Pten was globally required for retinal morphogenesis, histological sections of adult wild-type and Pten cKO retinas were analyzed. While the three cellular and two plexiform layers were readily visible in both wild-type and Pten mutant retinas (Figure 2A–D), several abnormalities were apparent in Pten cKOs, including: 1) a striking increase in retinal thickness; 2) a grossly expanded IPL populated by ectopic cells; 3) an expanded, loosely packed INL in which nuclei appeared larger, and 4) a thinner ONL. These results suggested that Pten may influence several events during retinal development, including cellular differentiation, cell migration, and neurite outgrowth and arborization, each of which was then individually investigated.


Cell-type specific roles for PTEN in establishing a functional retinal architecture.

Cantrup R, Dixit R, Palmesino E, Bonfield S, Shaker T, Tachibana N, Zinyk D, Dalesman S, Yamakawa K, Stell WK, Wong RO, Reese BE, Kania A, Sauvé Y, Schuurmans C - PLoS ONE (2012)

Abnormal retinal architecture and increased retinal cell sizes in Pten cKOs.(A–D) Low (A,B) and high (C,D) magnification images of hematoxylin-eosin (H&E) stained sections of adult wild-type (A,C) and Pten cKO (B,D) retinae. (E–G) Calbindin labelling of P7 wild-type and Pten cKO retinal sections (E,F) and area measurements of calbindin+ horizontal cells (G). (H–S) Labeling of retinal flatmounts from P21 wild-type and Pten cKOs with calbindin (H,I), ChAT (K,L), TH (N,O), and SMI32 (Q,R). Calculation of cell areas for P21 calbindin+ horizontal cells (J), ChAT+ (M) and calbindin+ (P) amacrine cells and SMI32+ RGCs (S). p values are denoted as follows: <0.05 *, <0.01 **, <0.005 ***. Scale bars = 100 µm (A,B,N,O), 50 µm (C–L,Q,R).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3293905&req=5

pone-0032795-g002: Abnormal retinal architecture and increased retinal cell sizes in Pten cKOs.(A–D) Low (A,B) and high (C,D) magnification images of hematoxylin-eosin (H&E) stained sections of adult wild-type (A,C) and Pten cKO (B,D) retinae. (E–G) Calbindin labelling of P7 wild-type and Pten cKO retinal sections (E,F) and area measurements of calbindin+ horizontal cells (G). (H–S) Labeling of retinal flatmounts from P21 wild-type and Pten cKOs with calbindin (H,I), ChAT (K,L), TH (N,O), and SMI32 (Q,R). Calculation of cell areas for P21 calbindin+ horizontal cells (J), ChAT+ (M) and calbindin+ (P) amacrine cells and SMI32+ RGCs (S). p values are denoted as follows: <0.05 *, <0.01 **, <0.005 ***. Scale bars = 100 µm (A,B,N,O), 50 µm (C–L,Q,R).
Mentions: To determine whether Pten was globally required for retinal morphogenesis, histological sections of adult wild-type and Pten cKO retinas were analyzed. While the three cellular and two plexiform layers were readily visible in both wild-type and Pten mutant retinas (Figure 2A–D), several abnormalities were apparent in Pten cKOs, including: 1) a striking increase in retinal thickness; 2) a grossly expanded IPL populated by ectopic cells; 3) an expanded, loosely packed INL in which nuclei appeared larger, and 4) a thinner ONL. These results suggested that Pten may influence several events during retinal development, including cellular differentiation, cell migration, and neurite outgrowth and arborization, each of which was then individually investigated.

Bottom Line: Furthermore, while Pten mutant RGC axons targeted appropriate brain regions, optokinetic spatial acuity was reduced in Pten mutant animals.We 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Hotchkiss Brain Institute, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.

ABSTRACT

Background: The 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 findings: In 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/significance: We 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.

Show MeSH
Related in: MedlinePlus