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Conditional expression of diphtheria toxin receptor (DTR) is widely used for tissue-specific ablation of cells. However, diphtheria toxin (DT) crosses the blood-brain barrier, which limits its utility for ablating peripheral cells using Cre drivers that are also expressed in the central nervous system (CNS). Here we report the development of a brain-sparing DT, termed BRAINSPAReDT, for tissue-specific genetic ablation of cells outside the CNS. We prevent blood-brain barrier passage of DT through PEGylation, which polarizes the molecule and increases its size. We validate BRAINSPAReDT with regional genetic sympathectomy: BRAINSPAReDT ablates peripheral but not central catecholaminergic neurons, thus avoiding the Parkinson-like phenotype associated with full dopaminergic depletion. Regional sympathectomy compromises adipose tissue thermogenesis, and renders mice susceptible to obesity. We provide a proof of principle that BRAINSPAReDT can be used for Cre/DTR tissue-specific ablation outside the brain using CNS drivers, while consolidating the link between adiposity and the sympathetic nervous system.

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Pereira, Mafalda M. A. -  Mahú, Inês -  Seixas, Elsa -  Martinéz -  Sánchez, Noelia -  Kubasova, Nadiya -  Pirzgalska, Roksana M -  Cohen, Paul -  Dietrich, Marcelo O -  López, Miguel -  Bernardes, Gonçalo J. L. -  Domingos, Ana I. - 

Id.: 69783636

Idioma: eng  - 

Versión: 1.0

Estado: Final

Palabras claveChemical modification - 

Tipo de recurso: article  - 

Tipo de Interactividad: Expositivo

Nivel de Interactividad: muy bajo

Audiencia: Estudiante  -  Profesor  -  Autor  - 

Estructura: Atomic

Coste: no

Copyright: sí

: openAccess

Requerimientos técnicos:  Browser: Any - 

Relación: [References] http://www.nature.com/articles/ncomms14967

Fecha de contribución: 12-abr-2017


* Pereira, M. M. A. et al. A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nat. Commun. 8, 14967 doi: 10.1038/ncomms14967 (2017).
* 10.1038/ncomms14967

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