Essential cell-intrinsic requirement for GMDS in T cell development
Fucosylation, a type of glycosylation, is the attachment of a fucose to N-glycans, O-glycans and glycolipids, and is critical for the post-translational regulation of many essential pathways. Here we describe a mouse strain with an N-ethyl-N-nitrosourea-induced point mutation in the gene encoding gu...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1598923/full |
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| author | Mehmet Yabas Mehmet Yabas Carla M. Roots T. Daniel Andrews Matt A. Field Matt A. Field Christopher C. Goodnow Christopher C. Goodnow Christopher C. Goodnow Anselm Enders |
| author_facet | Mehmet Yabas Mehmet Yabas Carla M. Roots T. Daniel Andrews Matt A. Field Matt A. Field Christopher C. Goodnow Christopher C. Goodnow Christopher C. Goodnow Anselm Enders |
| author_sort | Mehmet Yabas |
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| description | Fucosylation, a type of glycosylation, is the attachment of a fucose to N-glycans, O-glycans and glycolipids, and is critical for the post-translational regulation of many essential pathways. Here we describe a mouse strain with an N-ethyl-N-nitrosourea-induced point mutation in the gene encoding guanosine diphosphate (GDP)-mannose 4,6-dehydratase (GMDS), an enzyme involved in the generation of GDP-fucose, a substrate for fucosylation. GmdsY187*/Y187* mice displayed growth retardation and increased postnatal mortality. Immunophenotyping of GmdsY187*/Y187* mice revealed reduced numbers of double positive (DP), CD4 single positive (SP) and CD8SP T cells, despite normal numbers of double negative (DN) cells in the thymus of mutant animals. Similarly, analysis of the thymus in Rag1-/- mice reconstituted with GmdsY187*/Y187* bone marrow cells revealed a partial arrest at the DN stage of T cell development compared to animals transplanted with Gmds+/+ bone marrow cells. Furthermore, mixed chimeras showed that GmdsY187*/Y187* T cells were unable to compete with Gmds+/+ cells from the DP stage of T cell development in the thymus. This inability to compete resulted in the near absence of GmdsY187*/Y187*-derived peripheral T cells in recipient mice, while B cell subsets were present at broadly normal frequencies. These findings provide the first evidence of an essential cell-intrinsic requirement for GMDS in early T cell development in mice. |
| format | Article |
| id | doaj-art-e8c41c9a596f4feb943e154445c28bf0 |
| institution | Matheson Library |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj-art-e8c41c9a596f4feb943e154445c28bf02025-06-26T05:28:14ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.15989231598923Essential cell-intrinsic requirement for GMDS in T cell developmentMehmet Yabas0Mehmet Yabas1Carla M. Roots2T. Daniel Andrews3Matt A. Field4Matt A. Field5Christopher C. Goodnow6Christopher C. Goodnow7Christopher C. Goodnow8Anselm Enders9Division of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, AustraliaDepartment of Immunology, Faculty of Medicine, Malatya Turgut Ozal University, Malatya, TürkiyeDivision of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, AustraliaDivision of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, AustraliaCentre for Tropical Bioinformatics and Molecular Biology, College of Science and Engineering, James Cook University, Cairns, QLD, AustraliaThe Garvan Institute of Medical Research, Sydney, NSW, AustraliaDivision of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, AustraliaThe Garvan Institute of Medical Research, Sydney, NSW, AustraliaCellular Genomics Futures Institute, School of Biomedical Sciences, University of New South Wales, Sydney, NSW, AustraliaDivision of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, AustraliaFucosylation, a type of glycosylation, is the attachment of a fucose to N-glycans, O-glycans and glycolipids, and is critical for the post-translational regulation of many essential pathways. Here we describe a mouse strain with an N-ethyl-N-nitrosourea-induced point mutation in the gene encoding guanosine diphosphate (GDP)-mannose 4,6-dehydratase (GMDS), an enzyme involved in the generation of GDP-fucose, a substrate for fucosylation. GmdsY187*/Y187* mice displayed growth retardation and increased postnatal mortality. Immunophenotyping of GmdsY187*/Y187* mice revealed reduced numbers of double positive (DP), CD4 single positive (SP) and CD8SP T cells, despite normal numbers of double negative (DN) cells in the thymus of mutant animals. Similarly, analysis of the thymus in Rag1-/- mice reconstituted with GmdsY187*/Y187* bone marrow cells revealed a partial arrest at the DN stage of T cell development compared to animals transplanted with Gmds+/+ bone marrow cells. Furthermore, mixed chimeras showed that GmdsY187*/Y187* T cells were unable to compete with Gmds+/+ cells from the DP stage of T cell development in the thymus. This inability to compete resulted in the near absence of GmdsY187*/Y187*-derived peripheral T cells in recipient mice, while B cell subsets were present at broadly normal frequencies. These findings provide the first evidence of an essential cell-intrinsic requirement for GMDS in early T cell development in mice.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1598923/fullfucosylationglycosylationGMDSimmune systemT cellsT cell development |
| spellingShingle | Mehmet Yabas Mehmet Yabas Carla M. Roots T. Daniel Andrews Matt A. Field Matt A. Field Christopher C. Goodnow Christopher C. Goodnow Christopher C. Goodnow Anselm Enders Essential cell-intrinsic requirement for GMDS in T cell development Frontiers in Immunology fucosylation glycosylation GMDS immune system T cells T cell development |
| title | Essential cell-intrinsic requirement for GMDS in T cell development |
| title_full | Essential cell-intrinsic requirement for GMDS in T cell development |
| title_fullStr | Essential cell-intrinsic requirement for GMDS in T cell development |
| title_full_unstemmed | Essential cell-intrinsic requirement for GMDS in T cell development |
| title_short | Essential cell-intrinsic requirement for GMDS in T cell development |
| title_sort | essential cell intrinsic requirement for gmds in t cell development |
| topic | fucosylation glycosylation GMDS immune system T cells T cell development |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1598923/full |
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