Mechanobiology of Erythrocytes from Adult Mice Homozygous for a Targeted Disruption of the E-Tmod Gene at Exon 1

Green, Terrell; Vera, Carlos; Sussman, Mark A.; Martone, Maryann E.; Sung, Lanping Amy

doi:10.1007/s12195-011-0203-x

Cited by 5 publications

(4 citation statements)

References 30 publications

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“…While Tmod1 -/- mice died at embryonic day 9.5, the heterozygous Tmod1 +/- mice were able to mate with a cardiac specific Tmod1 overexpressing transgenic (TOT) mice ( 37 ). Interbreeding between their offsprings resulted in TOT/Tmod1 -/- mice where the overexpression of Tmod1 in the heart rescued the homozygosity’s lethality ( 38 ). TOT/Tmod1 -/- mice were transferred from Dr. L. Amy Sung’s lab to the Peking University Health Science Center and maintained in SPF animal room.…”

Section: Methodsmentioning

confidence: 99%

“…In the present study, we demonstrated that Tmod1 is expressed in bone marrow-derived dendritic cells (BMDCs) and is upregulated upon lipopolysaccharide (LPS)-induced DC maturation. Using BMDCs from TOT/Tmod1 -/- mice, that were obtained by crossing cardiomyocyte-specific Tmod1 overexpressing transgenic (TOT) mice with Tmod1 +/- mice ( 37 , 38 ), we showed that Tmod1 deficiency retarded DC maturation by downregulating the expression of costimulatory molecules and inflammatory cytokines, and impaired their migration and T-cell stimulatory abilities by altering their actin cytoskeleton and cell mechanics. Furthermore, LPS-treated Tmod1-deficient DCs secreted high levels of IFN-β and IL-10, and induced immune tolerance in an experimental autoimmune encephalomyelitis (EAE) mouse model.…”

Section: Introductionmentioning

confidence: 99%

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Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions

et al. 2021

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Dendritic cells (DCs) are the most potent antigen-presenting cells. Upon maturation, DCs express costimulatory molecules and migrate to the lymph nodes to present antigens to T cells. The actin cytoskeleton plays key roles in multiple aspects of DC functions. However, little is known about the mechanisms and identities of actin-binding proteins that control DC maturation and maturation-associated functional changes. Tropomodulin1 (Tmod1), an actin-capping protein, controls actin depolymerization and nucleation. We found that Tmod1 was expressed in bone marrow-derived immature DCs and was significantly upregulated upon lipopolysaccharide (LPS)-induced DC maturation. By characterizing LPS-induced mature DCs (mDCs) from Tmod1 knockout mice, we found that compared with Tmod1+/+ mDCs, Tmod1-deficient mDCs exhibited lower surface expression of costimulatory molecules and chemokine receptors and reduced secretion of inflammatory cytokines, suggesting that Tmod1 deficiency retarded DC maturation. Tmod1-deficient mDCs also showed impaired random and chemotactic migration, deteriorated T-cell stimulatory ability, and reduced F-actin content and cell stiffness. Furthermore, Tmod1-deficient mDCs secreted high levels of IFN-β and IL-10 and induced immune tolerance in an experimental autoimmune encephalomyelitis (EAE) mouse model. Mechanistically, Tmod1 deficiency affected TLR4 signaling transduction, resulting in the decreased activity of MyD88-dependent NFκB and MAPK pathways but the increased activity of the TRIF/IRF3 pathway. Rescue with exogenous Tmod1 reversed the effect of Tmod1 deficiency on TLR4 signaling. Therefore, Tmod1 is critical in regulating DC maturation and immune functions by regulating TLR4 signaling and the actin cytoskeleton. Tmod1 may be a potential target for modulating DC functions, a strategy that would be beneficial for immunotherapy for several diseases.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions

et al. 2021

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“…Yet the roles of Tmod1 in renal function remain unclear. Green et al bred Tmod1 + /lacZ mice with cardiomyocyte-specific Tmod1 overexpressing transgenic (TOT) mice to obtain TOT/Tmod1 lacZ/lacZ mice [18, 19], which made it possible to study the consequence of Tmod1 knockout in different cell types and tissues. But unfortunately, this mouse model is not suitable to study the renal function of Tmod1 since it develops dilated cardiomyopathy, which has abnormal vasopressin production [20].…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomics reveals TMOD1-related proteins associated with water balance regulation

Wang

Zhong

et al. 2019

PLoS ONE

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The distal tubule and collecting duct in kidney regulate water homeostasis. TMOD1 is an actin capping protein that plays an important role in controlling the organization of actin filaments. In this study, we found TMOD1 was specifically expressed in distal tubules and collecting ducts. To investigate the role of TMOD1, we created Tmod1 flox/flox mice and bred them with Ksp-Cre mice to generate tubule-specific Tmod1 knockout mice, Tmod1 flox/flox /Ksp-Cre + (designated as TFK). As compared with control mice, TFK mice showed oliguria, hyperosmolality urine, and high blood pressure. To determine the mechanisms underlying this phenotype, we performed label-free quantitative proteomics on kidneys of TFK and control mice. Total of 83 proteins were found differentially expressed. Bioinformatic analysis indicated that biological processes, including protein phosphorylation and metabolic process, were involved in TMOD1 regulatory network. Gene set enrichment analysis showed that multiple pathways, such as phosphatidylinositol signaling system and GnRH signaling pathway, were strongly associated with Tmod1 knockout. Western blot validated the down-regulation of three proteins, TGFBR2, SLC25A11, and MTFP1, in kidneys of TFK mice. Our study provides valuable information on the molecular functions and the regulatory network of Tmod1 gene in kidney, as well as the new mechanisms for the regulation of water balance.

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“…The expressions of E-Tmod41 and E-Tmod29 are driven by the alternative promoters of E-Tmod gene [ 7 ]. E-Tmod41 null mice display a mild sphero-elliptocytic anemia with osmotically fragile erythrocytes, due to the misregulation of F-actin lengths and a disrupted spectrin-actin lattice of membrane skeleton [ 8 , 9 ]. In addition to E-Tmod, there are three members in Tmod family, neuronal Tmod (N-Tmod), ubiquitous Tmod (U-Tmod), and skeletal muscle Tmod (sk-Tmod) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Fluid Shear Stress Upregulates E-Tmod41 via miR-23b-3p and Contributes to F-Actin Cytoskeleton Remodeling during Erythropoiesis

Wang

Zhang

et al. 2015

PLoS ONE

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The membrane skeleton of mature erythrocyte is formed during erythroid differentiation. Fluid shear stress is one of the main factors that promote embryonic hematopoiesis, however, its effects on erythroid differentiation and cytoskeleton remodeling are unclear. Erythrocyte tropomodulin of 41 kDa (E-Tmod41) caps the pointed end of actin filament (F-actin) and is critical for the formation of hexagonal topology of erythrocyte membrane skeleton. Our study focused on the regulation of E-Tmod41 and its role in F-actin cytoskeleton remodeling during erythroid differentiation induced by fluid shear stress. Mouse erythroleukemia (MEL) cells and embryonic erythroblasts were subjected to fluid shear stress (5 dyn/cm2) and erythroid differentiation was induced in both cells. F-actin content and E-Tmod41 expression were significantly increased in MEL cells after shearing. E-Tmod41 overexpression resulted in a significant increase in F-actin content, while the knockdown of E-Tmod41 generated the opposite result. An E-Tmod 3’UTR targeting miRNA, miR-23b-3p, was found suppressed by shear stress. When miR-23b-3p level was overexpressed / inhibited, both E-Tmod41 protein level and F-actin content were reduced / augmented. Furthermore, among the two alternative promoters of E-Tmod, PE0 (upstream of exon 0), which mainly drives the expression of E-Tmod41, was found activated by shear stress. In conclusion, our results suggest that fluid shear stress could induce erythroid differentiation and F-actin cytoskeleton remodeling. It upregulates E-Tmod41 expression through miR-23b-3p suppression and PE0 promoter activation, which, in turn, contributes to F-actin cytoskeleton remodeling.

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Mechanobiology of Erythrocytes from Adult Mice Homozygous for a Targeted Disruption of the E-Tmod Gene at Exon 1

Cited by 5 publications

References 30 publications

Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions

Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions

Quantitative proteomics reveals TMOD1-related proteins associated with water balance regulation

Fluid Shear Stress Upregulates E-Tmod41 via miR-23b-3p and Contributes to F-Actin Cytoskeleton Remodeling during Erythropoiesis

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