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Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development

In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)–induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell–independent (T...

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Autores principales: Choi, Jin Huk, Zhong, Xue, Zhang, Zhao, Su, Lijing, McAlpine, William, Misawa, Takuma, Liao, Tzu-Chieh, Zhan, Xiaoming, Russell, Jamie, Ludwig, Sara, Li, Xiaohong, Tang, Miao, Anderton, Priscilla, Moresco, Eva Marie Y., Beutler, Bruce
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144532/
https://www.ncbi.nlm.nih.gov/pubmed/31985756
http://dx.doi.org/10.1084/jem.20190006
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author Choi, Jin Huk
Zhong, Xue
Zhang, Zhao
Su, Lijing
McAlpine, William
Misawa, Takuma
Liao, Tzu-Chieh
Zhan, Xiaoming
Russell, Jamie
Ludwig, Sara
Li, Xiaohong
Tang, Miao
Anderton, Priscilla
Moresco, Eva Marie Y.
Beutler, Bruce
author_facet Choi, Jin Huk
Zhong, Xue
Zhang, Zhao
Su, Lijing
McAlpine, William
Misawa, Takuma
Liao, Tzu-Chieh
Zhan, Xiaoming
Russell, Jamie
Ludwig, Sara
Li, Xiaohong
Tang, Miao
Anderton, Priscilla
Moresco, Eva Marie Y.
Beutler, Bruce
author_sort Choi, Jin Huk
collection PubMed
description In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)–induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell–independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells.
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spelling pubmed-71445322020-10-06 Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development Choi, Jin Huk Zhong, Xue Zhang, Zhao Su, Lijing McAlpine, William Misawa, Takuma Liao, Tzu-Chieh Zhan, Xiaoming Russell, Jamie Ludwig, Sara Li, Xiaohong Tang, Miao Anderton, Priscilla Moresco, Eva Marie Y. Beutler, Bruce J Exp Med Brief Definitive Report In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)–induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell–independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide isomerase A6 (PDIA6), an oxidoreductase that functions in nascent protein folding in the endoplasmic reticulum. The immune deficiency caused by the Pdia6 mutation was, with the exception of a residual T cell developmental defect, completely rescued in irradiated wild-type recipients of PDIA6-deficient bone marrow cells, both in the absence or presence of competition. The viable hypomorphic allele uncovered in these studies reveals an essential role for PDIA6 in hematopoiesis, but one extrinsic to cells of the hematopoietic lineage. We show evidence that this role is in the proper folding of Wnt3a, BAFF, IL-7, and perhaps other factors produced by the extra-hematopoietic compartment that contribute to the development and lineage commitment of hematopoietic cells. Rockefeller University Press 2020-01-27 /pmc/articles/PMC7144532/ /pubmed/31985756 http://dx.doi.org/10.1084/jem.20190006 Text en © 2020 Choi et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Brief Definitive Report
Choi, Jin Huk
Zhong, Xue
Zhang, Zhao
Su, Lijing
McAlpine, William
Misawa, Takuma
Liao, Tzu-Chieh
Zhan, Xiaoming
Russell, Jamie
Ludwig, Sara
Li, Xiaohong
Tang, Miao
Anderton, Priscilla
Moresco, Eva Marie Y.
Beutler, Bruce
Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development
title Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development
title_full Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development
title_fullStr Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development
title_full_unstemmed Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development
title_short Essential cell-extrinsic requirement for PDIA6 in lymphoid and myeloid development
title_sort essential cell-extrinsic requirement for pdia6 in lymphoid and myeloid development
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144532/
https://www.ncbi.nlm.nih.gov/pubmed/31985756
http://dx.doi.org/10.1084/jem.20190006
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