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

Mafalda M. A. Pereira, Inês Mahú, Elsa Seixas, Noelia Martinéz-Sánchez, Nadiya Kubasova, Roksana M Pirzgalska, Paul Cohen, Marcelo O Dietrich, Miguel López, Gonçalo J. L. Bernardes and Ana I. Domingos ()
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Mafalda M. A. Pereira: Obesity Laboratory, Instituto Gulbenkian de Ciência
Inês Mahú: Obesity Laboratory, Instituto Gulbenkian de Ciência
Elsa Seixas: Obesity Laboratory, Instituto Gulbenkian de Ciência
Noelia Martinéz-Sánchez: NeurObesity Group, CIMUS, University of Santiago de Compostela—Instituto de Investigación Sanitaria
Nadiya Kubasova: Obesity Laboratory, Instituto Gulbenkian de Ciência
Roksana M Pirzgalska: Obesity Laboratory, Instituto Gulbenkian de Ciência
Paul Cohen: Laboratory of Molecular Metabolism, The Rockefeller University
Marcelo O Dietrich: Section of Comparative Medicine, Yale University School of Medicine
Miguel López: NeurObesity Group, CIMUS, University of Santiago de Compostela—Instituto de Investigación Sanitaria
Gonçalo J. L. Bernardes: University of Cambridge
Ana I. Domingos: Obesity Laboratory, Instituto Gulbenkian de Ciência

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14967

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