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Title: A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages
Author: 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.
Keywords: Chemical modification
Molecular neuroscience
Peripheral nervous system
Issue Date: 3-Apr-2017
Publisher: Nature Publishing Group
Citation: 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).
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.
Peer review: yes
DOI: 10.1038/ncomms14967
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