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Nat Commun. 2017 Apr 3;8:14967. doi: 10.1038/ncomms14967.

A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages.

Author information

1
Obesity Laboratory, Instituto Gulbenkian de Ciência, Oeiras 2780-156, Portugal.
2
NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela (A Coruña) 15782, Spain.
3
CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain.
4
Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York 10065, USA.
5
Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
6
Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
7
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
8
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa 1649-028, Portugal.

Abstract

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.

PMID:
28367972
PMCID:
PMC5382263
DOI:
10.1038/ncomms14967
[Indexed for MEDLINE]
Free PMC Article

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