Diphtheria toxin receptor–mediated conditional and targeted cell ablation in transgenic mice

Saito, Michiko; Iwawaki, Takao; Taya, Choji; Yonekawa, Hiromichi; Noda, Miki; Inui, Yoshiaki; Mekada, Eisuke; Kimata, Yukio; Tsuru, Akio; Kohno, Kenji

doi:10.1038/90795

Cited by 451 publications

(428 citation statements)

References 33 publications

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“…Using ARF‐DTR mice, we herein demonstrate that p19 ARF ‐expressing cells facilitate emphysema‐associated lung dysfunction. The elimination of p19 ARF ‐expressing cells by a toxin‐mediated cell knockout system (Saito et al, 2001) from lung tissue protected against elastase‐induced emphysema. Alveolar wall destruction was reduced, and pulmonary function was maintained, in the absence of p19 ARF ‐expressing cells.…”

Section: Introductionmentioning

confidence: 99%

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

et al. 2018

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Senescent cells accumulate in tissues during aging and are considered to underlie several aging‐associated phenotypes and diseases. We recently reported that the elimination of p19ARF‐expressing senescent cells from lung tissue restored tissue function and gene expression in middle‐aged (12‐month‐old) mice. The aging of lung tissue increases the risk of pulmonary diseases such as emphysema, and cellular senescence is accelerated in emphysema patients. However, there is currently no direct evidence to show that cellular senescence promotes the pathology of emphysema, and the involvement of senescence in the development of this disease has yet to be clarified. We herein demonstrated that p19ARF facilitated the development of pulmonary emphysema in mice. The elimination of p19ARF‐expressing cells prevented lung tissue from elastase‐induced lung dysfunction. These effects appeared to depend on reduced pulmonary inflammation, which is enhanced after elastase stimulation. Furthermore, the administration of a senolytic drug that selectively kills senescent cells attenuated emphysema‐associated pathologies. These results strongly suggest the potential of senescent cells as therapeutic/preventive targets for pulmonary emphysema.

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Section: Introductionmentioning

confidence: 99%

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

et al. 2018

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“…Once inside the cell, DTA inhibits protein biosynthesis and induces rapid cell death. The rodent homologue of HB-EGF precursor does not bind to the B subunit of DT, which prevents internalization of DTA and renders mice resistant to DT [28]. Transgenic expression of the high-affinity human HB-EGF precursor, henceforth referred to as DTR, in a particular murine cell type such as LC makes these cells sensitive to DT and enables their inducible depletion in vivo after exogenous introduction of DT.…”

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confidence: 99%

Insights into Langerhans cell function from Langerhans cell ablation models

2008

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Langerhans cells (LC) are the principal dendritic cell (DC) population in the epidermis of the skin. Owing to their prominent position at the environmental barrier, LC have long been considered to be prototypic sentinel DC. More recently, the precise role of LC in the initiation and control of cutaneous immune responses has become debatable. To elucidate their contribution to immune regulation in the skin, our laboratories have generated genetically modified mice in which LC can be followed in situ by expression of enhanced green fluorescent protein and can be either inducibly or constitutively depleted in vivo. This review highlights the similarities and differences between these mouse models, discusses the discovery and functional significance of Langerin 1 dermal DC, and examines some recent data that help to shed light on LC function. The Langerhans cell paradigmLangerhans cells (LC) were discovered by Paul Langerhans in 1868 [1], but it took more than 100 years before they were first associated with the immune system and recognized as antigenpresenting cells [2]. In particular, Ralph Steinman's group [3] dissected the functional characteristics of LC starting from the seminal finding that murine epidermal LC mature into potent immunostimulatory dendritic cells (DC) in vitro. The work that followed shaped the concept of DC as professional inducers of T-cell immune responses largely by studying LC, though the term 'LC paradigm' was coined much later by Wilson and Villadangos [4].This concept assigned three key functions to LC/DC (reviewed in [5]). First, immature LC that reside in the periphery in the steady state are highly specialized in antigen uptake. LC form a dense network in the epidermis where they constantly scan the environment by extending and retracting their dendrites and are ideally positioned to detect any pathogen breaching the skin barrier [6]. Second, LC transport antigen to skindraining lymph nodes (LN), which is essential to ensure interaction with rare antigen-specific naive T cells. Stimulation by a number of pathogen products in addition to pro-inflammatory cytokines induces LC activation [7][8][9]. Activated LC downregulate expression of E-cadherin, which is thought to maintain their position in the epidermis, and begin to express CC Correspondence: Daniel Kaplan e-mail: DanKaplan@umn.edu Eur. J. Immunol. 2008. 38: 2369-2376 DOI 10.1002 HIGHLIGHTS 2369 Mini-Reviewwww.eji-journal.eu chemokine receptor 7, which guides the cells to the T-cell areas in the LN. Third, during migration the LC undergo a process of maturation in which they process antigen acquired in the skin and present it in the context of MHC class I/II. In addition, they dramatically upregulate their surface expression of co-stimulatory molecules and start to produce cytokines required for proper Th1 or Th2 instruction. Thus, by the time LC arrive in the LN, they have acquired the surface phenotype of a 'functionally' mature DC capable of activating naive T cells and thereby initiating an adaptive immune response specif...

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“…The recent development of new transgenic mouse models expressing cytotoxic genes or specific toxin receptors has opened the door to more refined methods of Sertoli cell ablation (Palmiter et al ., 1987; Saito et al ., 2001; Buch et al ., 2005). Shinomura and colleagues (Shinomura et al ., 2014) and our group (Rebourcet et al ., 2014b) have independently applied similar approaches to drive the expression of diphtheria toxin A specifically in Sertoli cells from foetal life onwards, inducing Sertoli cell ablation from embryonic day 15.…”

Section: Sertoli Cellsmentioning

confidence: 99%

Cell‐specific ablation in the testis: what have we learned?

2015

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SummaryTesticular development and function is the culmination of a complex process of autocrine, paracrine and endocrine interactions between multiple cell types. Dissecting this has classically involved the use of systemic treatments to perturb endocrine function, or more recently, transgenic models to knockout individual genes. However, targeting genes one at a time does not capture the more wide‐ranging role of each cell type in its entirety. An often overlooked, but extremely powerful approach to elucidate cellular function is the use of cell ablation strategies, specifically removing one cellular population and examining the resultant impacts on development and function. Cell ablation studies reveal a more holistic overview of cell–cell interactions. This not only identifies important roles for the ablated cell type, which warrant further downstream study, but also, and importantly, reveals functions within the tissue that occur completely independently of the ablated cell type. To date, cell ablation studies in the testis have specifically removed germ cells, Leydig cells, macrophages and recently Sertoli cells. These studies have provided great leaps in understanding not possible via other approaches; as such, cell ablation represents an essential component in the researchers’ tool‐kit, and should be viewed as a complement to the more mainstream approaches to advancing our understanding of testis biology. In this review, we summarise the cell ablation models used in the testis, and discuss what each of these have taught us about testis development and function.

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Diphtheria toxin receptor–mediated conditional and targeted cell ablation in transgenic mice

Cited by 451 publications

References 33 publications

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

Insights into Langerhans cell function from Langerhans cell ablation models

Cell‐specific ablation in the testis: what have we learned?

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Diphtheria toxin receptor–mediated conditional and targeted cell ablation in transgenic mice

Cited by 451 publications

References 33 publications

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

Insights into Langerhans cell function from Langerhans cell ablation models

Cell‐specific ablation in the testis: what have we learned?

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Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice

Elimination of p19^ARF‐expressing cells protects against pulmonary emphysema in mice