An ENU-induced mutation in the lymphotoxin α gene impairs organogenesis of lymphoid tissues in C57BL/6 mice

Wang, Hongsheng; Feng, Jianxun; Qi, Chen‐Feng; Morse, Herbert C.

doi:10.1016/j.bbrc.2008.03.118

Cited by 5 publications

(2 citation statements)

References 28 publications

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“…Although ENU mutagenesis usually generates point mutations resulting in single base changes, insertion mutations have been reported previously. 17,18 In fact, one-or two-base insertion mutation occurred up to 37% in one series. 19 Both Western blotting (not shown) and immunofluorescence provided evidence that the sglt2 protein is not expressed in proximal tubules of Sweet Pee mutants.…”

Section: Discussionmentioning

confidence: 89%

The Sweet Pee Model for Sglt2 Mutation

Onay

Sison

et al. 2011

Journal of the American Society of Nephrology

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Inhibiting renal glucose transport is a potential pharmacologic approach to treat diabetes. The renal tubular sodium-glucose transporter 2 (SGLT2) reabsorbs approximately 90% of the filtered glucose load. An animal model with sglt2 dysfunction could provide information regarding the potential long-term safety and efficacy of SGLT2 inhibitors, which are currently under clinical investigation. Here, we describe Sweet Pee, a mouse model that carries a nonsense mutation in the Slc5a2 gene, which results in the loss of sglt2 protein function. The phenotype of Sweet Pee mutants was remarkably similar to patients with mutations in the Scl5a2 gene. The Sweet Pee mutants had improved glucose tolerance, higher urinary excretion of calcium and magnesium, and growth retardation. Renal physiologic studies demonstrated a prominent distal osmotic diuresis without enhanced natriuresis. Sweet Pee mutants did not exhibit increased KIM-1 or NGAL, markers of acute tubular injury. After induction of diabetes, Sweet Pee mice had better overall glycemic control than wild-type control mice, but had a higher risk for infection and an increased mortality rate (70% in homozygous mutants versus 10% in controls at 20 weeks). In summary, the Sweet Pee model allows study of the long-term benefits and risks associated with inhibition of SGLT2 for the management of diabetes. Our model suggests that inhibiting SGLT2 may improve glucose control but may confer increased risks for infection, malnutrition, volume contraction, and mortality.

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Section: Discussionmentioning

confidence: 89%

The Sweet Pee Model for Sglt2 Mutation

Onay

Sison

et al. 2011

Journal of the American Society of Nephrology

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“…These mice also show abnormal splenic architecture with defective segregation of B and T cells. Mice harboring a point mutation induced by N-ethyl-N-nitrosourea (ENU) in the Lta gene also lack LN and Peyer's patches and display disorganized splenic architecture [12]. Similarly Ltb-and Ltbr-deficient mice lack LN and Peyer's patches and have disrupted splenic organization [13,14].…”

Section: Introductionmentioning

confidence: 99%

Lymphotoxin: from the physiology to the regeneration of the thymic function

Borelli

Irla

2021

Cell Death Differ

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The members of the Tumor Necrosis Factor (TNF) superfamily, the ligand lymphotoxin α1β2 (LTα1β2) and its unique receptor lymphotoxin β receptor (LTβR), play a pivotal role in the establishment and regulation of the immune system by allowing a tight communication between lymphocytes and stromal cells. Recent advances using transgenic mice harboring a specific deletion of the Ltbr gene in distinct stromal cells have revealed important roles for LTβR signaling in the thymic function that ensures the generation of a diverse and self-tolerant T-cell repertoire. In this review, we summarize our current knowledge on this signaling axis in the thymic homing of lymphoid progenitors and peripheral antigen-presenting cells, the trafficking and egress of thymocytes, the differentiation of medullary thymic epithelial cells, and the establishment of central tolerance. We also highlight the importance of LTα1β2/LTβR axis in controlling the recovery of the thymic function after myeloablative conditioning regimen, opening novel perspectives in regenerative medicine.

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B-lymphocyte tolerance and effector function in immunity and autoimmunity

et al. 2013

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B-lymphocytes are integral to host defense against microbial pathogens and are associated with many autoimmune diseases. The B-cell receptor implements B-cell self-tolerance based on the antigen specificity, and B-cell-activating factor receptor (BAFF-R) imposes homeostatic control. While shaping the repertoire, the immune tolerance process also culls mature B cells into distinct populations. The activation response of B cells is tailored to the type of pathogen attack and is facilitated by T-cell help via CD40/CD40L interaction and/or innate cell help via toll-like receptors in conjunction with BAFF receptors and ligands. Activated effector B cells not only produce antibodies, but also produce a variety of cytokines to enhance and suppress the immune response. Not surprisingly, B cells play multiple roles in both humoral and cellular immune responses during infection and autoimmune pathogenesis. Here, we discuss how gene expression and signaling networks regulate peripheral B-cell tolerance, B-cell effector functions and emerging therapies targeting B-cell signaling in autoimmune diseases.

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An ENU-induced mutation in the lymphotoxin α gene impairs organogenesis of lymphoid tissues in C57BL/6 mice

Cited by 5 publications

References 28 publications

The Sweet Pee Model for Sglt2 Mutation

The Sweet Pee Model for Sglt2 Mutation

Lymphotoxin: from the physiology to the regeneration of the thymic function

B-lymphocyte tolerance and effector function in immunity and autoimmunity

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