CUED Publications database

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

Pereira, MMA and Mahú, I and Seixas, E and Martinéz-Sánchez, N and Kubasova, N and Pirzgalska, RM and Cohen, P and Dietrich, MO and López, M and Bernardes, GJL and Domingos, AI (2017) A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages. Nature Communications, 8. 14967-.

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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.

Item Type: Article
Uncontrolled Keywords: Animals Brain Cell Lineage Diphtheria Toxin Disease Susceptibility Energy Metabolism Feeding Behavior Female Gene Deletion Gene Expression Regulation Glucose Intolerance HeLa Cells Humans Hydrodynamics Male Mice Movement Neurons Norepinephrine Obesity Parkinson Disease Polyethylene Glycols Sympathectomy Thermogenesis
Depositing User: Cron Job
Date Deposited: 17 Jul 2019 20:18
Last Modified: 13 Apr 2021 07:42
DOI: 10.1038/ncomms14967