Pten regulates endocytic trafficking of cell adhesion and Wnt signaling molecules to pattern the retina

Yacine Touahri; Joseph Hanna; Nobuhiko Tachibana; Satoshi Okawa; Hedy Liu; Luke Ajay David; Thomas Olender; Lakshmy Vasan; Alissa Pak; Dhruv Nimesh Mehta; Vorapin Chinchalongporn; Anjali Balakrishnan; Robert Cantrup; Rajiv Dixit; Pierre Mattar; Fermisk Saleh; Yaroslav Ilnytskyy; Monzur Murshed; Paul E Mains; Igor Kovalchuk; Julie L Lefebvre; Hon S Leong; Michel Cayouette; Chao Wang; Antonio Del Sol; Marjorie Brand; Benjamin E Reese; Carol Schuurmans

doi:10.1016/j.celrep.2024.114005

Pten regulates endocytic trafficking of cell adhesion and Wnt signaling molecules to pattern the retina

Cell Rep. 2024 Apr 23;43(4):114005. doi: 10.1016/j.celrep.2024.114005. Epub 2024 Mar 27.

Authors

Yacine Touahri¹, Joseph Hanna², Nobuhiko Tachibana³, Satoshi Okawa⁴, Hedy Liu⁵, Luke Ajay David², Thomas Olender⁶, Lakshmy Vasan⁷, Alissa Pak⁷, Dhruv Nimesh Mehta¹, Vorapin Chinchalongporn⁵, Anjali Balakrishnan⁸, Robert Cantrup⁹, Rajiv Dixit⁵, Pierre Mattar¹⁰, Fermisk Saleh⁵, Yaroslav Ilnytskyy¹¹, Monzur Murshed¹², Paul E Mains⁹, Igor Kovalchuk¹¹, Julie L Lefebvre¹³, Hon S Leong¹⁴, Michel Cayouette¹⁰, Chao Wang¹⁵, Antonio Del Sol¹⁶, Marjorie Brand⁶, Benjamin E Reese¹⁷, Carol Schuurmans¹⁸

Affiliations

¹ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5T 3A9, Canada.
² Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5T 3A9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
³ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁴ Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg; Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
⁵ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁶ Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON K1H 8L6, Canada.
⁷ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁸ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
⁹ Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
¹⁰ Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC H2W 1R7, Canada.
¹¹ Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada.
¹² Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC H3G 1A6, Canada.
¹³ Department of Molecular Genetics, University of Toronto, Toronto ON M5S 1A8, Canada; Program for Neuroscience and Mental Health, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
¹⁴ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
¹⁵ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Immunology, University of Toronto, Toronto, ON M5G 1L7, Canada.
¹⁶ Computational Biology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 4362 Esch-sur-Alzette, Luxembourg; CIC bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain; IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain.
¹⁷ Department of Psychological and Brain Sciences, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106-5060, USA.
¹⁸ Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5T 3A9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: cschuurm@sri.utoronto.ca.

Abstract

The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and tensin homolog (Pten) controls starburst amacrine cell spacing by modulating vesicular trafficking of cell adhesion molecules and Wnt proteins. Single-cell transcriptomics and double-mutant analyses revealed that Pten and Down syndrome cell adhesion molecule Dscam) are co-expressed and function additively to pattern starburst amacrine cell mosaics. Mechanistically, Pten loss accelerates the endocytic trafficking of DSCAM, FAT3, and MEGF10 off the cell membrane and into endocytic vesicles in amacrine cells. Accordingly, the vesicular proteome, a molecular signature of the cell of origin, is enriched in exocytosis, vesicle-mediated transport, and receptor internalization proteins in Pten conditional knockout (Pten^cKO) retinas. Wnt signaling molecules are also enriched in Pten^cKO retinal vesicles, and the genetic or pharmacological disruption of Wnt signaling phenocopies amacrine cell patterning defects. Pten thus controls vesicular trafficking of cell adhesion and signaling molecules to establish retinal amacrine cell mosaics.

Keywords: CP: Cell biology; CP: Developmental biology; DSCAM; PTEN phosphatase; Wnt signaling; cell adhesion molecules; endocytic recycling; extracellular vesicles; retinal mosaics; starburst amacrine cells.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Amacrine Cells* / metabolism
Animals
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism
Cell Adhesion*
Endocytosis*
Mice
Mice, Knockout
PTEN Phosphohydrolase* / genetics
PTEN Phosphohydrolase* / metabolism
Protein Transport
Retina* / metabolism
Wnt Proteins / metabolism
Wnt Signaling Pathway*

Substances

PTEN Phosphohydrolase
Pten protein, mouse
Wnt Proteins
Cell Adhesion Molecules

Grants and funding

R01 EY019968/EY/NEI NIH HHS/United States