Pei-Ciao Tang, Seyoung Um, Anderson B Mayfield, Olena R Bracho, Christian Del Castillo, Christine T Dinh, Derek M Dykxhoorn, Xue Zhong Liu
{"title":"Merlin、Arkadia和SKOR2之间的相互作用介导nf2相关的人类雪旺细胞增殖。","authors":"Pei-Ciao Tang, Seyoung Um, Anderson B Mayfield, Olena R Bracho, Christian Del Castillo, Christine T Dinh, Derek M Dykxhoorn, Xue Zhong Liu","doi":"10.1186/s13287-025-04281-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>NF2-related Schwannomatosis (previously referred to as Neurofibromatosis Type 2, or NF2) is a genetic-associated disease resulting from mutations in the gene, NF2. NF2 encodes the Merlin protein, which acts as a tumor suppressor. Bilateral vestibular schwannoma (VS) is a hallmark of NF2. Although the exactly molecular mechanism mediating NF2-driven schwannomatosis is not fully understood, it is known that defective Merlin protein functionality leads to abnormal cell proliferation.</p><p><strong>Methods: </strong>Herein, we utilized a human induced pluripotent stem cell (hiPSC)-based Schwann cell (SC) model to investigate the role of Merlin in human SCs. SCs were derived from hiPSCs carrying a NF2 mutation (c.191 T > C; p. L64P), its isogenic wild-type control cell line, and a NF2 patient-derived hiPSC line. Phenotypes were determined via immunocytochemistry and various bioassays. Different proteins interacting with Merlin in wild-type and NF2 mutation SCs were identified using co-immunoprecipitation followed by mass spectrometry.</p><p><strong>Results: </strong>SC derived from NF2<sup>L64P</sup> hiPSCs showed significantly higher proliferation and abnormal morphology compared to NF2<sup>WT</sup> SCs. Phenotypes that could be restored by wildtype NF2 overexpression. Interactome profiling of Merlin (NF2) in SCs derived from NF2<sup>WT</sup>- and NF2<sup>L64P</sup>- hiPCSs identified differential protein binding levels. Among identified proteins, we validated the interaction among Merlin, an E3 ubiquitin ligase (Arkadia), and a SKI family co-repressor (SKOR2). This complex plays a significant role for this interaction in SC proliferation. Our findings were further validated by SCs derived from the patient-derived hiPSCs carrying a deletion in the chromosome 22 which spans the NF2 gene.</p><p><strong>Conclusions: </strong>Our results presented a hiPSC-derived SC system for SC-related disease modeling and established a new model in which Merlin interacts with Arkadia and SKOR2. This interaction is required for the proper cell proliferation in human SCs.</p>","PeriodicalId":21876,"journal":{"name":"Stem Cell Research & Therapy","volume":"16 1","pages":"163"},"PeriodicalIF":7.1000,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972516/pdf/","citationCount":"0","resultStr":"{\"title\":\"Interactions among Merlin, Arkadia, and SKOR2 mediate NF2-associated human Schwann cell proliferation.\",\"authors\":\"Pei-Ciao Tang, Seyoung Um, Anderson B Mayfield, Olena R Bracho, Christian Del Castillo, Christine T Dinh, Derek M Dykxhoorn, Xue Zhong Liu\",\"doi\":\"10.1186/s13287-025-04281-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>NF2-related Schwannomatosis (previously referred to as Neurofibromatosis Type 2, or NF2) is a genetic-associated disease resulting from mutations in the gene, NF2. NF2 encodes the Merlin protein, which acts as a tumor suppressor. Bilateral vestibular schwannoma (VS) is a hallmark of NF2. Although the exactly molecular mechanism mediating NF2-driven schwannomatosis is not fully understood, it is known that defective Merlin protein functionality leads to abnormal cell proliferation.</p><p><strong>Methods: </strong>Herein, we utilized a human induced pluripotent stem cell (hiPSC)-based Schwann cell (SC) model to investigate the role of Merlin in human SCs. SCs were derived from hiPSCs carrying a NF2 mutation (c.191 T > C; p. L64P), its isogenic wild-type control cell line, and a NF2 patient-derived hiPSC line. Phenotypes were determined via immunocytochemistry and various bioassays. Different proteins interacting with Merlin in wild-type and NF2 mutation SCs were identified using co-immunoprecipitation followed by mass spectrometry.</p><p><strong>Results: </strong>SC derived from NF2<sup>L64P</sup> hiPSCs showed significantly higher proliferation and abnormal morphology compared to NF2<sup>WT</sup> SCs. Phenotypes that could be restored by wildtype NF2 overexpression. Interactome profiling of Merlin (NF2) in SCs derived from NF2<sup>WT</sup>- and NF2<sup>L64P</sup>- hiPCSs identified differential protein binding levels. Among identified proteins, we validated the interaction among Merlin, an E3 ubiquitin ligase (Arkadia), and a SKI family co-repressor (SKOR2). This complex plays a significant role for this interaction in SC proliferation. Our findings were further validated by SCs derived from the patient-derived hiPSCs carrying a deletion in the chromosome 22 which spans the NF2 gene.</p><p><strong>Conclusions: </strong>Our results presented a hiPSC-derived SC system for SC-related disease modeling and established a new model in which Merlin interacts with Arkadia and SKOR2. This interaction is required for the proper cell proliferation in human SCs.</p>\",\"PeriodicalId\":21876,\"journal\":{\"name\":\"Stem Cell Research & Therapy\",\"volume\":\"16 1\",\"pages\":\"163\"},\"PeriodicalIF\":7.1000,\"publicationDate\":\"2025-04-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972516/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Stem Cell Research & Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13287-025-04281-x\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Stem Cell Research & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13287-025-04281-x","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
Interactions among Merlin, Arkadia, and SKOR2 mediate NF2-associated human Schwann cell proliferation.
Background: NF2-related Schwannomatosis (previously referred to as Neurofibromatosis Type 2, or NF2) is a genetic-associated disease resulting from mutations in the gene, NF2. NF2 encodes the Merlin protein, which acts as a tumor suppressor. Bilateral vestibular schwannoma (VS) is a hallmark of NF2. Although the exactly molecular mechanism mediating NF2-driven schwannomatosis is not fully understood, it is known that defective Merlin protein functionality leads to abnormal cell proliferation.
Methods: Herein, we utilized a human induced pluripotent stem cell (hiPSC)-based Schwann cell (SC) model to investigate the role of Merlin in human SCs. SCs were derived from hiPSCs carrying a NF2 mutation (c.191 T > C; p. L64P), its isogenic wild-type control cell line, and a NF2 patient-derived hiPSC line. Phenotypes were determined via immunocytochemistry and various bioassays. Different proteins interacting with Merlin in wild-type and NF2 mutation SCs were identified using co-immunoprecipitation followed by mass spectrometry.
Results: SC derived from NF2L64P hiPSCs showed significantly higher proliferation and abnormal morphology compared to NF2WT SCs. Phenotypes that could be restored by wildtype NF2 overexpression. Interactome profiling of Merlin (NF2) in SCs derived from NF2WT- and NF2L64P- hiPCSs identified differential protein binding levels. Among identified proteins, we validated the interaction among Merlin, an E3 ubiquitin ligase (Arkadia), and a SKI family co-repressor (SKOR2). This complex plays a significant role for this interaction in SC proliferation. Our findings were further validated by SCs derived from the patient-derived hiPSCs carrying a deletion in the chromosome 22 which spans the NF2 gene.
Conclusions: Our results presented a hiPSC-derived SC system for SC-related disease modeling and established a new model in which Merlin interacts with Arkadia and SKOR2. This interaction is required for the proper cell proliferation in human SCs.
期刊介绍：
Stem Cell Research & Therapy serves as a leading platform for translational research in stem cell therapies. This international, peer-reviewed journal publishes high-quality open-access research articles, with a focus on basic, translational, and clinical research in stem cell therapeutics and regenerative therapies. Coverage includes animal models and clinical trials. Additionally, the journal offers reviews, viewpoints, commentaries, and reports.
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