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A Pig-a conditional knock-out mice model mediated by Vav-iCre: stable GPI-deficient and mild hemolysis.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria is a clonal disease caused by PIG-A mutation of hematopoietic stem cells. At present, there is no suitable PNH animal model for basic research, therefore, it is urgent to establish a stable animal model. We constructed a Pig-a conditional knock-out mice model by ES targeting technique and Vav-iCre. The expressions of GPI and GPI-AP were almost completely absent in CKO homozygote mice, and the proportion of the deficiency remained stable from birth. In CKO heterozygote mice, the proportion of the deficiency of GPI and GPI-AP was partially absent and decreased gradually from birth until it reached a stable level at 3 months after birth and remained there for life. Compared with normal C57BL/6N mice and Flox mice, pancytopenia was found in CKO homozygous mice, and leukopenia and anemia were found in CKO heterozygotes mice. Meanwhile, in CKO mice, the serum LDH, TBIL, IBIL, complement C5b-9 levels were increased, and the concentration of plasma FHb was increased. Hemosiderin granulosa cells can be seen more easily in the spleens of CKO mice. What's more, CKO mice had stable transcription characteristics. In conclusion, our mouse model has stable GPI-deficient and mild hemolysis, which may be an ideal in vivo experimental model for PNH.

SUBMITTER: Chen Y

PROVIDER: S-EPMC8760646 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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A Pig-a conditional knock-out mice model mediated by Vav-iCre: stable GPI-deficient and mild hemolysis.

Chen Yingying Y Liu Hui H Zeng Lijie L Li Liyan L Lu Dan D Liu Zhaoyun Z Fu Rong R

Experimental hematology & oncology 20220115 1

Paroxysmal nocturnal hemoglobinuria is a clonal disease caused by PIG-A mutation of hematopoietic stem cells. At present, there is no suitable PNH animal model for basic research, therefore, it is urgent to establish a stable animal model. We constructed a Pig-a conditional knock-out mice model by ES targeting technique and Vav-iCre. The expressions of GPI and GPI-AP were almost completely absent in CKO homozygote mice, and the proportion of the deficiency remained stable from birth. In CKO hete ...[more]

PMID: 35033195

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Project description:FIP200 (focal adhesion kinase family interacting protein of 200 kDa) has been shown to interact with other proteins to regulate several intracellular signaling pathways. To study a potential role of FIP200 in tumorigenesis and possibly other disease processes in vivo, we created and analyzed murine mammary tumor virus-Cre-mediated FIP200 conditional knock-out (CKO) mice. We found that deletion of FIP200 in mammary epithelial cells did not result in spontaneous development of breast cancer. Moreover, deletion of FIP200 did not further accelerate or inhibit lymphomagenesis induced by inactivation of p53 in mice. Interestingly, however, FIP200 and p53 double conditional knock-out (dCKO) mice exhibited significant hyperplasia of epidermis (acanthosis), thickening of the cornified layer (hyperkeratosis), and increased vascularity in the dermis. FIP200 CKO mice also showed similar, although less severe, skin defects as dCKO mice. Analyses of primary keratinocytes isolated from dCKO mice did not detect increased proliferation of these cells in vitro, suggesting that epidermis hyperproliferation is not epidermal cell-autonomous but may be a consequence of increased inflammation triggered by immune cells in vivo. Consistent with this possibility, we found infiltration of leukocytes including T cells, macrophages, and granulocytes into the dermis and epidermis, associated with activation of NF-kappaB and increased expression of several proinflammatory cytokines and chemokines in skin of the dCKO mice. We further found that cultured FIP200 KO keratinocytes showed reduced NF-kappaB phosphorylation in response to tumor necrosis factor alpha stimulation, suggesting a paracrine regulation of aberrant NF-kappaB activation in the skin microenviroment of dCKO and FIP200 CKO mice. Together, these results demonstrate that ablation of FIP200, although not promoting tumorigenesis, can lead to skin inflammatory disorders, suggesting a novel function of FIP200 in the maintenance of normal skin homeostasis in vivo.

Dataset Information

A Pig-a conditional knock-out mice model mediated by Vav-iCre: stable GPI-deficient and mild hemolysis.

Publications

A Pig-a conditional knock-out mice model mediated by Vav-iCre: stable GPI-deficient and mild hemolysis.

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