An ENU-induced mouse mutant of SHIP1 reveals a critical role of the stem cell isoform for suppression of macrophage activation

Nguyen, NYN; Maxwell, MJ; Ooms, LM; Davies, EM; Hilton, AA; Collinge, JE; Hilton, DJ; Kile, BT; Mitchell, CA; Hibbs, ML; Jane, SM; Curtis, DJ

Author(s): Nguyen, NYN; Maxwell, MJ; Ooms, LM; Davies, EM; Hilton, AA; Collinge, JE; Hilton, DJ; Kile, BT; Mitchell, CA; Hibbs, ML; Jane, SM; Curtis, DJ;
Details: Publication Year 2011-05-19,Volume 117,Issue #20,Page 5362-5371
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: In a recessive ENU mutagenesis screen for embryonic lethality, we identified a mouse pedigree with a missense mutation of SHIP1 (SHIP1(el20)) leading to an amino acid substitution I641T in the inositol-5'-phosphatase domain that represses phosphatidylinositol-3-kinase signaling. Despite detectable expression of functional SHIP1 protein, the phenotype of homozygous SHIP1(el20/el20) mice was more severe than gene-targeted SHIP1-null (SHIP1(-/-)) mice. Compared with age-matched SHIP1(-/-) mice, 5-week-old SHIP1(el20/el20) mice had increased myeloid cells, serum IL-6 levels, marked reductions in lymphoid cells, and died by 7 weeks of age with infiltration of the lungs by activated macrophages. Bone marrow transplantation demonstrated that these defects were hematopoietic-cell-autonomous. We show that the el20 mutation reduces expression in SHIP1(el20/el20) macrophages of both SHIP1 and s-SHIP, an isoform of SHIP1 generated by an internal promoter. In contrast, SHIP1(-/-) macrophages express normal levels of s-SHIP. Compound heterozygous mice (SHIP1(-/el20)) had the same phenotype as SHIP1(-/-) mice, thus providing genetic proof that the more severe phenotype of SHIP1(el20/el20) mice is probably the result of concomitant loss of SHIP1 and s-SHIP. Our results suggest that s-SHIP synergizes with SHIP1 for suppression of macrophage activation, thus providing the first evidence for a role of s-SHIP in adult hematopoiesis. (Blood. 2011;117(20):5362-5371)
Publisher: AMER SOC HEMATOLOGY
Keywords: INOSITOL PHOSPHATASE SHIP; FC-GAMMA-RIIB; DEFICIENT MICE; BONE-MARROW; IN-VIVO; POLYPHOSPHATE 5-PHOSPHATASE; NEGATIVE REGULATOR; B-LYMPHOCYTES; MAST-CELLS; PROTEIN
Publisher's Version: https://doi.org/10.1182/blood-2011-01-331041
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Creation Date: 2011-05-19 12:00:00