The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway
PAT1 homolog 2 (PATL2), encoding an RNA-binding protein, is a repressor involved in the translational regulation of maternal mRNAs during oocyte maturation. Previous studies have reported mutations in PATL2 those led to female infertility with oocyte maturation arrest; however, the mechanisms by whi...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.628649/full |
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| author | Qiqi Cao Chun Zhao Congjing Wang Lingbo Cai Meng Xia Xiaolan Zhang Jian Han Yangyang Xu Junqiang Zhang Xiufeng Ling Xiang Ma Ran Huo Ran Huo |
| author_facet | Qiqi Cao Chun Zhao Congjing Wang Lingbo Cai Meng Xia Xiaolan Zhang Jian Han Yangyang Xu Junqiang Zhang Xiufeng Ling Xiang Ma Ran Huo Ran Huo |
| author_sort | Qiqi Cao |
| collection | DOAJ |
| description | PAT1 homolog 2 (PATL2), encoding an RNA-binding protein, is a repressor involved in the translational regulation of maternal mRNAs during oocyte maturation. Previous studies have reported mutations in PATL2 those led to female infertility with oocyte maturation arrest; however, the mechanisms by which mutations affected meiotic maturation remained unclear. Here, we identified several novel and recurrent mutations of PATL2 in patients with similar phenotype, and chose the missense mutation c.649 T>A p.Tyr217Asn in PATL2 (PATL2Y217N) as a typical to investigate the underlying mechanisms. We confirmed that this mutation disturbed oocyte maturation and observed morphological defects of large polar body, symmetrical division and abnormal spindle after microinjection of corresponding mutated mRNA. We further evaluated the effect of the PATL2Y217N mutation in 293T cells, and found this mutation decreased the ubiquitination level and degradation of PATL2. Then, abnormally increased PATL2 bound mRNAs of Mos, an upstream activator of mitogen activated protein kinase (MAPK), to regulate its translational activity and subsequently impaired MAPK signaling pathway and oocyte meiosis. These results dissented from the previous view that PATL2 mutations reduced their expression and highlight the role of PATL2 in translational regulation of Mos and its association with MAPK signaling pathway during oocyte meiotic maturation. |
| first_indexed | 2024-12-18T00:31:37Z |
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| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-18T00:31:37Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-7d7942606be842458d2f9721ca147ade2022-12-21T21:27:06ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-02-01910.3389/fcell.2021.628649628649The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK PathwayQiqi Cao0Chun Zhao1Congjing Wang2Lingbo Cai3Meng Xia4Xiaolan Zhang5Jian Han6Yangyang Xu7Junqiang Zhang8Xiufeng Ling9Xiang Ma10Ran Huo11Ran Huo12State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Suzhou Affiliated Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, ChinaDepartment of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, ChinaState Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Suzhou Affiliated Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, ChinaClinical Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaClinical Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, ChinaState Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Suzhou Affiliated Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, ChinaClinical Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaDepartment of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, ChinaDepartment of Reproductive Medicine, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, ChinaClinical Center of Reproductive Medicine, State Key Laboratory of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, ChinaState Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Suzhou Affiliated Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, ChinaCenter for Global Health, School of Public Health, Nanjing Medical University, Nanjing, ChinaPAT1 homolog 2 (PATL2), encoding an RNA-binding protein, is a repressor involved in the translational regulation of maternal mRNAs during oocyte maturation. Previous studies have reported mutations in PATL2 those led to female infertility with oocyte maturation arrest; however, the mechanisms by which mutations affected meiotic maturation remained unclear. Here, we identified several novel and recurrent mutations of PATL2 in patients with similar phenotype, and chose the missense mutation c.649 T>A p.Tyr217Asn in PATL2 (PATL2Y217N) as a typical to investigate the underlying mechanisms. We confirmed that this mutation disturbed oocyte maturation and observed morphological defects of large polar body, symmetrical division and abnormal spindle after microinjection of corresponding mutated mRNA. We further evaluated the effect of the PATL2Y217N mutation in 293T cells, and found this mutation decreased the ubiquitination level and degradation of PATL2. Then, abnormally increased PATL2 bound mRNAs of Mos, an upstream activator of mitogen activated protein kinase (MAPK), to regulate its translational activity and subsequently impaired MAPK signaling pathway and oocyte meiosis. These results dissented from the previous view that PATL2 mutations reduced their expression and highlight the role of PATL2 in translational regulation of Mos and its association with MAPK signaling pathway during oocyte meiotic maturation.https://www.frontiersin.org/articles/10.3389/fcell.2021.628649/fullmeiotic maturationPATL2 mutationARTMAPKfemale infertility |
| spellingShingle | Qiqi Cao Chun Zhao Congjing Wang Lingbo Cai Meng Xia Xiaolan Zhang Jian Han Yangyang Xu Junqiang Zhang Xiufeng Ling Xiang Ma Ran Huo Ran Huo The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway Frontiers in Cell and Developmental Biology meiotic maturation PATL2 mutation ART MAPK female infertility |
| title | The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway |
| title_full | The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway |
| title_fullStr | The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway |
| title_full_unstemmed | The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway |
| title_short | The Recurrent Mutation in PATL2 Inhibits Its Degradation Thus Causing Female Infertility Characterized by Oocyte Maturation Defect Through Regulation of the Mos-MAPK Pathway |
| title_sort | recurrent mutation in patl2 inhibits its degradation thus causing female infertility characterized by oocyte maturation defect through regulation of the mos mapk pathway |
| topic | meiotic maturation PATL2 mutation ART MAPK female infertility |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.628649/full |
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