A hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia.
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.
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, Marseille, France.
Diana
D
Ordoñez-Rueda
Friederike
F
Jönsson
David A
DA
Mancardi
Weidong
W
Zhao
Aurélie
A
Malzac
Yinming
Y
Liang
Elodie
E
Bertosio
Pierre
P
Grenot
Véronique
V
Blanquet
Sybille
S
Sabrautzki
Martin Hrabě
MH
de Angelis
Stéphane
S
Méresse
Estelle
E
Duprez
Pierre
P
Bruhns
Bernard
B
Malissen
Marie
M
Malissen
D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D001168:Arthritis / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005038:Ethylnitrosourea; D005260:Female; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009503:Neutropenia / Q000139:chemically induced / Q000235:genetics*; D009504:Neutrophils / Q000378:metabolism; D017354:Point Mutation; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
D000950:Antigens, Ly; D039481:CD11b Antigen; D004268:DNA-Binding Proteins; C079873:Gfi1 protein, mouse; C480309:Ly6G antigen, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D005038:Ethylnitrosourea