Genetic inversion in mast cell-deficient (Wsh) mice interrupts corin and manifests as hematopoietic and cardiac aberrancy.
Mast cells participate in pathophysiological processes that range from antimicrobial defense to anaphylaxis and inflammatory arthritis. Much of the groundwork for the understanding of mast cells was established in mice that lacked mast cells through defects in either stem cell factor or its receptor, Kit. Among available strains, C57BL/6-Kit(W-sh) (W(sh)) mice are experimentally advantageous because of their background strain and fertility. However, the genetic inversion responsible for the W(sh) phenotype remains poorly defined, and its effects beyond the mast cell have been incompletely characterized. We report that W(sh) animals exhibit splenomegaly with expanded myeloid and megakaryocyte populations. Hematopoietic abnormalities extend to the bone marrow and are reflected by neutrophilia and thrombocytosis. In contrast, mast cell-deficient WBB6F1-Kit(W)/Kit(W-v) (W/W(v)) mice display mild neutropenia, but no changes in circulating platelet numbers. To help define the basis for the W(sh) phenotype, a "DNA walking" strategy was used to identify the precise location of the 3' breakpoint, which was found to reside 67.5 kb upstream of Kit. The 5' breakpoint disrupts corin, a cardiac protease responsible for the activation of atrial natriuretic peptide. Consistent with this result, transcription of full-length corin is ablated and W(sh) mice develop symptoms of cardiomegaly. Studies performed using mast cell-deficient strains must consider the capacity of associated abnormalities to either expose or compensate for the missing mast cell lineage.
Nigrovic
Peter A
PA
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA 02115, USA.
Gray
Daniel H D
DH
Jones
Tatiana
T
Hallgren
Jenny
J
Kuo
Frank C
FC
Chaletzky
Blair
B
Gurish
Michael
M
Mathis
Diane
D
Benoist
Christophe
C
Lee
David M
DM
D000818:Animals; D007446:Chromosome Inversion; D006321:Heart / Q000502:physiology*; D006330:Heart Defects, Congenital / Q000235:genetics*; D006413:Hematopoietic System / Q000002:abnormalities / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000002:abnormalities / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D019009:Proto-Oncogene Proteins c-kit; C485617:Corin protein, mouse; D012697:Serine Endopeptidases