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      Rer1-mediated quality control system is required for neural stem cell maintenance during cerebral cortex development

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          Abstract

          Rer1 is a retrieval receptor for endoplasmic reticulum (ER) retention of various ER membrane proteins and unassembled or immature components of membrane protein complexes. However, its physiological functions during mammalian development remain unclear. This study aimed to investigate the role of Rer1-mediated quality control system in mammalian development. We show that Rer1 is required for the sufficient cell surface expression and activity of γ-secretase complex, which modulates Notch signaling during mouse cerebral cortex development. When Rer1 was depleted in the mouse cerebral cortex, the number of neural stem cells decreased significantly, and malformation of the cerebral cortex was observed. Rer1 loss reduced γ-secretase activity and downregulated Notch signaling in the developing cerebral cortex. In Rer1-deficient cells, a subpopulation of γ-secretase complexes and components was transported to and degraded in lysosomes, thereby significantly reducing the amount of γ-secretase complex on the cell surface. These results suggest that Rer1 maintains Notch signaling by maintaining sufficient expression of the γ-secretase complex on the cell surface and regulating neural stem cell maintenance during cerebral cortex development.

          Author summary

          We showed that Rer1 functions as an early-Golgi quality control pathway that maintains γ-secretase activity by maintaining sufficient cell surface expression of γ-secretase complex during cerebral cortex development, thereby modulating Notch signaling.

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          Most cited references36

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          Retrovirus-mediated gene transfer and expression cloning: powerful tools in functional genomics.

          Most of the human genome has now been sequenced and about 30,000 potential open reading frames have been identified, indicating that we use these 30,000 genes to functionally organize our biologic activities. However, functions of many genes are still unknown despite intensive efforts using bioinformatics as well as transgenic and knockout mice. Retrovirus-mediated gene transfer is a powerful tool that can be used to understand gene functions. We have developed a variety of retrovirus vectors and efficient packaging cell lines that have facilitated the development of efficient functional expression cloning methods. In this review, we describe retrovirus-mediated strategies used for investigation of gene functions and function-based screening strategies.
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            Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans.

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              Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.

              The majority of early-onset cases of familial Alzheimer's disease (FAD) are linked to mutations in two related genes, PS1 and PS2, located on chromosome 14 and 1, respectively. Using two highly specific antibodies against nonoverlapping epitopes of the PS1-encoded polypeptide, termed presenilin 1 (PS1), we document that the preponderant PS1-related species that accumulate in cultured mammalian cells, and in the brains of rodents, primates, and humans are approximately 27-28 kDa N-terminal and approximately 16-17 kDa C-terminal derivatives. Notably, a FAD-linked PS1 variant that lacks exon 9 is not subject to endoproteolytic cleavage. In brains of transgenic mice expressing human PS1, approximately 17 kDa and approximately 27 kDa PS1 derivatives accumulate to saturable levels, and at approximately 1:1 stoichiometry, independent of transgene-derived mRNA. We conclude that PS1 is subject to endoproteolytic processing in vivo.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: ValidationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Formal analysisRole: InvestigationRole: Methodology
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, CA USA )
                1553-7390
                1553-7404
                27 September 2018
                September 2018
                : 14
                : 9
                : e1007647
                Affiliations
                [1 ] Laboratory of Molecular Traffic, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan
                [2 ] Laboratory of Cellular Regulation, Faculty of Human Sciences, Waseda University, Mikajima, Tokorozawa, Saitama, Japan
                [3 ] Laboratory Animal and Genome Sciences Section, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
                Stanford University School of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-1034-5091
                Article
                PGENETICS-D-17-01995
                10.1371/journal.pgen.1007647
                6159856
                30260951
                0df3e550-3531-4efb-9d9e-3a331f97cda4
                © 2018 Hara et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 October 2017
                : 20 August 2018
                Page count
                Figures: 5, Tables: 0, Pages: 22
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;
                Award Recipient :
                Funded by: Nakajima Foundation
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100007263, Astellas Foundation for Research on Metabolic Disorders;
                Award Recipient :
                Funded by: MEXT JSPS KAKENHI
                Award ID: 17K08621, 15K19002, 24116702 and 24590341
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009619, Japan Agency for Medical Research and Development;
                Award ID: 26310301
                Award Recipient :
                Funded by: JSPS KAKENHI
                Award ID: 17K19377, 17H03669
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100008732, Uehara Memorial Foundation;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;
                Award Recipient :
                Funded by: Waseda University Grant for Special research Project
                Award ID: 2017S-142, 2018K-349
                Award Recipient :
                TH was supported by research grants from the Takeda Science Foundation( http://www.takeda-sci.or.jp/), the Nakajima Foundation( http://www.nakajimafound.or.jp/), the Astellas Foundation for Research on Metabolic Disorders( https://www.astellas.com/jp/byoutai/), and MEXT JSPS KAKENHI (Grant Number:17K08621( https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17K08621), 15K19002 ( https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15K19002/),24116702 ( https://kaken.nii.ac.jp/grant/KAKENHI-PUBLICLY-24116702/), and 24590341( https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-24590341/). This research is also supported by the research program for conquering intractable disease from Japan Agency for Medical Research and Development, AMED(Grant Number 26310301, http://www.amed.go.jp/en/) and is a part pf the outcome of research performed under a Waseda University Grant for Special Research Project (Project number: 2017S-142 and 2018K-349). KS was supported by the JSPS KAKENHI (Grant Number: 17K19377, 17H03669), the Uehara Memorial Foundation, and Takeda Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Brain
                Cerebral Cortex
                Medicine and Health Sciences
                Anatomy
                Brain
                Cerebral Cortex
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Notch Signaling
                Research and Analysis Methods
                Histochemistry and Cytochemistry Techniques
                Immunohistochemistry Techniques
                Research and Analysis Methods
                Immunologic Techniques
                Immunohistochemistry Techniques
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Lysosomes
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Membrane Proteins
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblot Analysis
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Probe Techniques
                Immunoblot Analysis
                Research and Analysis Methods
                Specimen Preparation and Treatment
                Staining
                Immunostaining
                Biology and Life Sciences
                Anatomy
                Brain
                Cerebrum
                Medicine and Health Sciences
                Anatomy
                Brain
                Cerebrum
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Genetics
                Genetics

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