Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice
Background The NDUFS4 gene encodes an 18-kD subunit of mitochondria complex I, and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans. To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the Ndufs4 k...
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PeerJ Inc.
2017-05-01
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| author | Mei Wang Ya-Ping Huang Han Wu Ke Song Cong Wan A-Ni Chi Ya-Mei Xiao Xiao-Yang Zhao |
| author_facet | Mei Wang Ya-Ping Huang Han Wu Ke Song Cong Wan A-Ni Chi Ya-Mei Xiao Xiao-Yang Zhao |
| author_sort | Mei Wang |
| collection | DOAJ |
| description | Background The NDUFS4 gene encodes an 18-kD subunit of mitochondria complex I, and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans. To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the Ndufs4 knockout (KO) mouse has been widely used as a novel animal model. Because the homozygotes cannot survive beyond child-bearing age, whether Ndufs4 and mitochondrial complex I influence early embryonic development remains unknown. In our study, we attempted to investigate embryonic development in Ndufs4 KO mice, which can be regarded as a Leigh disease model and were created through the CRISPR (clustered regularly interspaced short palindromic repeat) and Cas9 (CRISPR associated)-mediated genome editing system. Methods We first designed a single guide RNA (sgRNA) targeting exon 2 of Ndufs4 to delete the NDUFS4 protein in mouse embryos to mimic Leigh syndrome. Then, we described the phenotypes of our mouse model by forced swimming and the open-field test as well as by assessing other behavioral characteristics. Intracytoplasmic sperm injection (ICSI) was performed to obtain KO embryos to test the influence of NDUFS4 deletion on early embryonic development. Results In this study, we first generated Ndufs4 KO mice with physical and behavioral phenotypes similar to Leigh syndrome using the CRISPR/Cas9 system. The low developmental rate of KO embryos that were derived from knockout gametes indicated that the absence of NDUFS4 impaired the development of preimplantation embryos. Discussion In this paper, we first obtained Ndufs4 KO mice that could mimic Leigh syndrome using the CRISPR/Cas9 system. Then, we identified the role of NDUFS4 in early embryonic development, shedding light on its roles in the respiratory chain and fertility. Our model provides a useful tool with which to investigate the function of Ndufs4. Although the pathological mechanisms of the disease need to be discovered, it helps to understand the pathogenesis of NDUFS4 deficiency in mice and its effects on human diseases. |
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| last_indexed | 2024-03-09T06:58:40Z |
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| spelling | doaj.art-f798bf7798bb41d2a31a765bb4743e722023-12-03T10:02:01ZengPeerJ Inc.PeerJ2167-83592017-05-015e333910.7717/peerj.3339Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout miceMei Wang0Ya-Ping Huang1Han Wu2Ke Song3Cong Wan4A-Ni Chi5Ya-Mei Xiao6Xiao-Yang Zhao7State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, ChinaDepartment of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaSchool of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaDepartment of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaDepartment of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaState Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, ChinaDepartment of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, ChinaBackground The NDUFS4 gene encodes an 18-kD subunit of mitochondria complex I, and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans. To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the Ndufs4 knockout (KO) mouse has been widely used as a novel animal model. Because the homozygotes cannot survive beyond child-bearing age, whether Ndufs4 and mitochondrial complex I influence early embryonic development remains unknown. In our study, we attempted to investigate embryonic development in Ndufs4 KO mice, which can be regarded as a Leigh disease model and were created through the CRISPR (clustered regularly interspaced short palindromic repeat) and Cas9 (CRISPR associated)-mediated genome editing system. Methods We first designed a single guide RNA (sgRNA) targeting exon 2 of Ndufs4 to delete the NDUFS4 protein in mouse embryos to mimic Leigh syndrome. Then, we described the phenotypes of our mouse model by forced swimming and the open-field test as well as by assessing other behavioral characteristics. Intracytoplasmic sperm injection (ICSI) was performed to obtain KO embryos to test the influence of NDUFS4 deletion on early embryonic development. Results In this study, we first generated Ndufs4 KO mice with physical and behavioral phenotypes similar to Leigh syndrome using the CRISPR/Cas9 system. The low developmental rate of KO embryos that were derived from knockout gametes indicated that the absence of NDUFS4 impaired the development of preimplantation embryos. Discussion In this paper, we first obtained Ndufs4 KO mice that could mimic Leigh syndrome using the CRISPR/Cas9 system. Then, we identified the role of NDUFS4 in early embryonic development, shedding light on its roles in the respiratory chain and fertility. Our model provides a useful tool with which to investigate the function of Ndufs4. Although the pathological mechanisms of the disease need to be discovered, it helps to understand the pathogenesis of NDUFS4 deficiency in mice and its effects on human diseases.https://peerj.com/articles/3339.pdfMitochondria complex INdufs4CRISPR/Cas9Embryo development |
| spellingShingle | Mei Wang Ya-Ping Huang Han Wu Ke Song Cong Wan A-Ni Chi Ya-Mei Xiao Xiao-Yang Zhao Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice PeerJ Mitochondria complex I Ndufs4 CRISPR/Cas9 Embryo development |
| title | Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice |
| title_full | Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice |
| title_fullStr | Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice |
| title_full_unstemmed | Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice |
| title_short | Mitochondrial complex I deficiency leads to the retardation of early embryonic development in Ndufs4 knockout mice |
| title_sort | mitochondrial complex i deficiency leads to the retardation of early embryonic development in ndufs4 knockout mice |
| topic | Mitochondria complex I Ndufs4 CRISPR/Cas9 Embryo development |
| url | https://peerj.com/articles/3339.pdf |
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