Targeted disruption of SHIP leads to hemopoietic perturbations, lung pathology, and a shortened life span
Open accessAbstract
SHIP is a 145-kD SH 2-containing i nositol-5-p hosphatase widely expressed in hemopoietic cells. It was first identified as a tyrosine phosphoprotein associated with Shc in response to numerous cytokines. SHIP has been implicated in FcγRIIB receptor-mediated negative signaling in B cells and mast cells and is postulated to down-regulate cytokine signal transduction in myeloid cells. To define further its role in the proliferation and differentiation of hemopoietic progenitors, as well as its function in mature cells, we have generated embryonic stem cells and mice bearing a targeted disruption of both SHIP alleles. Here we show that although SHIP null mice are viable and fertile, they fail to thrive and survival is only 40% by 14 weeks of age. Mortality is associated with extensive consolidation of the lungs resulting from infiltration by myeloid cells. Increased numbers of granulocyte–macrophage progenitors are observed in both the bone marrow and spleen of SHIP−/−mice, perhaps as a consequence of hyper-responsiveness to stimulation by macrophage–colony stimulating factor, granulocyte–macrophage colony stimulating factor, interleukin-3, or Steel factor as observed in vitro. In contrast, numbers of bone marrow lymphoid and late erythroid progenitors (CFU-E) are reduced. Thus, homozygous disruption of SHIP establishes the crucial role of this molecule in modulating cytokine signaling within the hemopoietic system and provides a powerful model for further delineating its function.
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Conditional Inpp5d knockdown in microglia avoids the developmental effects that can occur in constitutive knockouts.
“This strategy also avoids the developmental effects that can occur in constitutive knockouts.16,17”
From Microglial <i>INPP5D</i> limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease (2023) · cites this paper as [17]
The SHIP gene-targeting section describes a germline knockout, and the section on SHIP−/− mice failing to thrive reports reduced body weight and splenomegaly by 4–5 weeks of age. These findings support the concern that constitutive loss has early-life effects, but the paper does not examine microglia or show that conditional knockdown avoids developmental effects. (LLM, conf=0.79)
Experimental — accuracy not yet measuredGermline ubiquitous knockout of INPP5D in mice leads to overproliferation of peripheral myeloid cells that results in early postnatal lethality.
“Germline ubiquitous knockout of this gene in mice leads to the overproliferation of peripheral myeloid cells that results in early postnatal lethality [53].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [53]
The targeted-disruption section describes SHIP-null mice, and the shortened-life-span section reports deaths beginning at four weeks, with over half dead by ten weeks. The Discussion links early death most likely to lung impairment from myeloid-cell infiltration, but does not establish overproliferation of peripheral myeloid cells as the cause; it also says grossly elevated peripheral white-cell counts were not seen. The mice were viable and fertile, so the claim overstates the lethality. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSHIP1 negatively regulates myeloid cell proliferation.
“previous reports showing that SHIP1 negatively regulates myeloid cell proliferation52,53.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [52]
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- Authors
- Helgason, C. D., Damen, J. E., Rosten, P., Grewal, R., Sorensen, P., Chappel, S. M., Borowski, A., Jirik, F., Krystal, G., & Humphries, R. K.
- Affiliations
- BC Cancer Agency (CA)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-06-01
- Volume
- 12
- Issue
- 11
- Pages
- 1610-1620
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC316868
- OpenAlex
- W2107425729
- Cited by
- 556
- References
- 3
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 3 · 2023: 13 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 7 · 2016: 12 · 2015: 24 · 2014: 11 · 2013: 18 · 2012: 36
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Medical Research Council
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- ships, targeted gene disruption, hematopoiesis, hematopoietic progenitor cells, CFU-GM, CFU-E, cytokine signaling, myeloid cell infiltration, lung consolidation, survival, embryonic stem cells, Fcγ receptor signaling, Shc, macrophage colony-stimulating factor, interleukin-3, stem cell factor
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Hematopoiesis, Longevity, Lung, Phosphoric Monoester Hydrolases, Mice, Knockout, Gene Expression Regulation, Developmental, src Homology Domains, Mice
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