MC4R mutant mice develop ovarian teratomas

Abstract Teratomas in mice, composed of different tissue types, are derived from primordial germ cells (PGCs) in the foetal gonads. The strongest candidate gene in the testicular teratoma locus (Ter) responsible for testicular teratoma formation was identified as mutation in Dnd1, Dnd1R178*. However...

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Autores principales:	Abdullah An Naser, Takehiro Miyazaki, Jun Wang, Shuji Takabayashi, Theeranukul Pachoensuk, Toshinobu Tokumoto
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Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5996f2d8a8b848b0ba9bcf02e4f85438
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spelling	oai:doaj.org-article:5996f2d8a8b848b0ba9bcf02e4f854382021-12-02T12:14:56ZMC4R mutant mice develop ovarian teratomas10.1038/s41598-021-83001-w2045-2322https://doaj.org/article/5996f2d8a8b848b0ba9bcf02e4f854382021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83001-whttps://doaj.org/toc/2045-2322Abstract Teratomas in mice, composed of different tissue types, are derived from primordial germ cells (PGCs) in the foetal gonads. The strongest candidate gene in the testicular teratoma locus (Ter) responsible for testicular teratoma formation was identified as mutation in Dnd1, Dnd1R178*. However, the phenotype of mice with a mutated Dnd1 gene was germ cell loss. This suggests that other genes are involved in teratoma formation. Testicular teratomas can also be induced experimentally (experimentally testicular teratomas: ETTs) in 129/Sv mice by transplanting E12.5 foetal testes into adult testes. Previously, we mapped the ett1 locus, which is the locus responsible for ETT formation on chromosome 18. By exome sequence analysis of the 129 and LTXBJ (LT) strains, we identified a missense mutation in the melanocortin 4 receptor (MC4R) gene among 8 genes in the ett1 region. The missense mutation causes a substitution of glycine 25 by serine. Thus, this gene is a candidate for ETT formation. We established the LT-ett1 congenic strain, which introduced the locus responsible for ETT formation genetically into the genomes of a testicular teratoma non-susceptible strain. In this study, we crossed LT-ett1 and a previously established LT-Ter strain to establish the double congenic strain LT-Ter-ett1. Also, we established a strain with a point mutation in the MC4R gene of the LT strain by genome editing, LT-MC4R G25S . Furthermore, double genetically modified strain LT-Ter-MC4R G25S was established to address the relation between Ter and MC4R. Surprisingly, highly developed ovarian teratomas (OTs), instead of testicular teratomas, appeared not only in the LT-Ter-MC4R G25S and LT-MC4R G25S strains but also in the LT-ett1 and LT-Ter-ett1 strains. The incidence of OT formation was high in double genetically modified strains. The results demonstrated that MC4R is one of the genes responsible for OT formation. It was suggested that the effect of the missense mutation in MC4R on teratoma formation was promoted by abnormal germ cell formation by the mutation in DND1.Abdullah An NaserTakehiro MiyazakiJun WangShuji TakabayashiTheeranukul PachoensukToshinobu TokumotoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abdullah An Naser Takehiro Miyazaki Jun Wang Shuji Takabayashi Theeranukul Pachoensuk Toshinobu Tokumoto MC4R mutant mice develop ovarian teratomas
description	Abstract Teratomas in mice, composed of different tissue types, are derived from primordial germ cells (PGCs) in the foetal gonads. The strongest candidate gene in the testicular teratoma locus (Ter) responsible for testicular teratoma formation was identified as mutation in Dnd1, Dnd1R178*. However, the phenotype of mice with a mutated Dnd1 gene was germ cell loss. This suggests that other genes are involved in teratoma formation. Testicular teratomas can also be induced experimentally (experimentally testicular teratomas: ETTs) in 129/Sv mice by transplanting E12.5 foetal testes into adult testes. Previously, we mapped the ett1 locus, which is the locus responsible for ETT formation on chromosome 18. By exome sequence analysis of the 129 and LTXBJ (LT) strains, we identified a missense mutation in the melanocortin 4 receptor (MC4R) gene among 8 genes in the ett1 region. The missense mutation causes a substitution of glycine 25 by serine. Thus, this gene is a candidate for ETT formation. We established the LT-ett1 congenic strain, which introduced the locus responsible for ETT formation genetically into the genomes of a testicular teratoma non-susceptible strain. In this study, we crossed LT-ett1 and a previously established LT-Ter strain to establish the double congenic strain LT-Ter-ett1. Also, we established a strain with a point mutation in the MC4R gene of the LT strain by genome editing, LT-MC4R G25S . Furthermore, double genetically modified strain LT-Ter-MC4R G25S was established to address the relation between Ter and MC4R. Surprisingly, highly developed ovarian teratomas (OTs), instead of testicular teratomas, appeared not only in the LT-Ter-MC4R G25S and LT-MC4R G25S strains but also in the LT-ett1 and LT-Ter-ett1 strains. The incidence of OT formation was high in double genetically modified strains. The results demonstrated that MC4R is one of the genes responsible for OT formation. It was suggested that the effect of the missense mutation in MC4R on teratoma formation was promoted by abnormal germ cell formation by the mutation in DND1.
format	article
author	Abdullah An Naser Takehiro Miyazaki Jun Wang Shuji Takabayashi Theeranukul Pachoensuk Toshinobu Tokumoto
author_facet	Abdullah An Naser Takehiro Miyazaki Jun Wang Shuji Takabayashi Theeranukul Pachoensuk Toshinobu Tokumoto
author_sort	Abdullah An Naser
title	MC4R mutant mice develop ovarian teratomas
title_short	MC4R mutant mice develop ovarian teratomas
title_full	MC4R mutant mice develop ovarian teratomas
title_fullStr	MC4R mutant mice develop ovarian teratomas
title_full_unstemmed	MC4R mutant mice develop ovarian teratomas
title_sort	mc4r mutant mice develop ovarian teratomas
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5996f2d8a8b848b0ba9bcf02e4f85438
work_keys_str_mv	AT abdullahannaser mc4rmutantmicedevelopovarianteratomas AT takehiromiyazaki mc4rmutantmicedevelopovarianteratomas AT junwang mc4rmutantmicedevelopovarianteratomas AT shujitakabayashi mc4rmutantmicedevelopovarianteratomas AT theeranukulpachoensuk mc4rmutantmicedevelopovarianteratomas AT toshinobutokumoto mc4rmutantmicedevelopovarianteratomas
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MC4R mutant mice develop ovarian teratomas

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