A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration

Buch, Thorsten; Heppner, Frank L.; Tertilt, Christine; Heinen, Tobias; Kremer, Marcel; Wunderlich, Frank; Jung, Steffen; Waisman, Ari

doi:10.1038/nmeth762

Cited by 770 publications

(743 citation statements)

References 48 publications

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“…The main stumbling block will be achieving a high enough level of expression in an inducible manner. To study the requirement for a certain cell type, the combination of GIFM and cellular phenotyping alleles harboring LoxP-STOP-diphtheria toxic (DT) A fragment or its receptor (e.g., Buch et al, 2005;Ivanova et al, 2005) will allow for the ablation of a genetically defined population of cells (Fig. 3D).…”

Section: Future Prospects For Using Gifm To Analyze Cell Morphology mentioning

confidence: 99%

Genetic inducible fate mapping in mouse: Establishing genetic lineages and defining genetic neuroanatomy in the nervous system

Joyner

Zervas

2006

Developmental Dynamics

172

167

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A fascinating aspect of developmental biology is how organs are assembled in three dimensions over time. Fundamental to understanding organogenesis is the ability to determine when and where specific cell types are generated, the lineage of each cell, and how cells move to reside in their final position. Numerous methods have been developed to mark and follow the fate of cells in various model organisms used by developmental biologists, but most are not readily applicable to mouse embryos in utero because they involve physical marking of cells through injection of tracers. The advent of sophisticated transgenic and gene targeting techniques, combined with the use of site-specific recombinases, has revolutionized fate mapping studies in mouse. Furthermore, using genetic fate mapping to mark cells has opened up the possibility of addressing fundamental questions that cannot be studied with traditional methods of fate mapping in other organisms. Specifically, genetic fate mapping allows both the relationship between embryonic gene expression and cell fate (genetic lineage) to be determined, as well as the link between gene expression domains and anatomy (genetic anatomy) to be established. In this review, we present the ever-evolving development of genetic fate mapping techniques in mouse, especially the recent advance of Genetic Inducible Fate Mapping. We then review recent studies in the nervous system (focusing on the anterior hindbrain) as well as in the limb and with adult stem cells to highlight fundamental developmental processes that can be discovered using genetic fate mapping approaches. We end with a look toward the future at a powerful new approach that combines genetic fate mapping with cellular phenotyping alleles to study cell morphology, physiology, and function using examples from the nervous system. Developmental Dynamics 235:2376 -2385, 2006.

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Section: Future Prospects For Using Gifm To Analyze Cell Morphology mentioning

confidence: 99%

Genetic inducible fate mapping in mouse: Establishing genetic lineages and defining genetic neuroanatomy in the nervous system

Joyner

Zervas

2006

Developmental Dynamics

172

167

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“…For example, mice do not normally express diphtheria toxin receptor [181,182]. Conditional expression of the receptor allows only the genetically modified cells to take up the toxin.…”

Section: Cell-specific Neurotoxinsmentioning

confidence: 99%

Selective Manipulation of Neural Circuits

Park

Carmel

2016

Neurotherapeutics

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Unraveling the complex network of neural circuits that form the nervous system demands tools that can manipulate specific circuits. The recent evolution of genetic tools to target neural circuits allows an unprecedented precision in elucidating their function. Here we describe two general approaches for achieving circuit specificity. The first uses the genetic identity of a cell, such as a transcription factor unique to a circuit, to drive expression of a molecule that can manipulate cell function. The second uses the spatial connectivity of a circuit to achieve specificity: one genetic element is introduced at the origin of a circuit and the other at its termination. When the two genetic elements combine within a neuron, they can alter its function. These two general approaches can be combined to allow manipulation of neurons with a specific genetic identity by introducing a regulatory gene into the origin or termination of the circuit. We consider the advantages and disadvantages of both these general approaches with regard to specificity and efficacy of the manipulations. We also review the genetic techniques that allow gain-and loss-of-function within specific neural circuits. These approaches introduce light-sensitive channels (optogenetic) or drug sensitive channels (chemogenetic) into neurons that form specific circuits. We compare these tools with others developed for circuit-specific manipulation and describe the advantages of each. Finally, we discuss how these tools might be applied for identification of the neural circuits that mediate behavior and for repair of neural connections.

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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%

“…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. In addition, we have also combined an Amh‐Cre line (Lecureuil et al ., 2002) and a iDTR line (Buch et al ., 2005) to permit ablation of Sertoli cells via injection of DTX (Rebourcet et al ., 2014a,b) (Fig. 2).…”

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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A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration

Cited by 770 publications

References 48 publications

Genetic inducible fate mapping in mouse: Establishing genetic lineages and defining genetic neuroanatomy in the nervous system

Genetic inducible fate mapping in mouse: Establishing genetic lineages and defining genetic neuroanatomy in the nervous system

Selective Manipulation of Neural Circuits

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

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