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Ordoñez-Rueda, D.* ; Jönsson, F.* ; Mancardi, D.A.* ; Zhao, W.* ; Malzac, A.* ; Liang, Y.* ; Bertosio, E.* ; Grenot, P.* ; Blanquet, V.* ; Sabrautzki, S. ; Hrabě de Angelis, M. ; Méresse, S.* ; Duprez, E.* ; Bruhns, P.* ; Malissen, B.* ; Malissen, M.*

A hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia.

Eur. J. Immunol. 42, 2395-2408 (2012)
Postprint DOI PMC
Open Access Green
Using N-ethyl-N-nitrosourea-induced mutagenesis, we established a mouse model with a novel form of neutropenia resulting from a point mutation in the transcriptional repressor Growth Factor Independence 1 (Gfi1). These mice, called Genista, had normal viability and no weight loss, in contrast to mice expressing null alleles of the Gfi1 gene. Furthermore, the Genista mutation had a very limited impact on lymphopoiesis or on T- and B-cell function. Within the bone marrow (BM), the Genista mutation resulted in a slight increase of monopoiesis and in a block of terminal granulopoiesis. This block occurred just after the metamyelocytic stage and resulted in the generation of small numbers of atypical CD11b(+) Ly-6G(int) neutrophils, the nuclear morphology of which resembled that of mature WT neutrophils. Unexpectedly, once released from the BM, these atypical neutrophils contributed to induce mild forms of autoantibody-induced arthritis and of immune complex-mediated lung alveolitis. They additionally failed to provide resistance to acute bacterial infection. Our study demonstrates that a hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia characterized by a split pattern of functional responses, reflecting the distinct thresholds required for eliciting neutrophil-mediated inflammatory and anti-infectious responses.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bacterial infection; Functional genomics; Inflammation; Mouse model; Neutrophils; HEMATOPOIETIC STEM-CELLS; LYMPHOCYTE DEVELOPMENT; MOUSE MODEL; SALMONELLA; PROTEIN; INNATE; INFLAMMATION; NEUTROPHILS; INFECTION; MICE
ISSN (print) / ISBN 0014-2980
e-ISSN 1521-4141
Journal European Journal of Immunology
Quellenangaben Volume: 42, Issue: 9, Pages: 2395-2408 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Hoboken
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)