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

• DOI: 10.1038/ncomms14967
• Publication Date: 2017-04-03T09:39:10Z
• Authors: Mafalda M. A. Per...; Inês Mahú; Elsa Seixas; Noelia Martinéz-S...; Nadiya Kubasova; Roksana M Pirzgalska; Paul Cohen; Marcelo O Dietrich; Miguel López; Gonçalo J. L. Ber...; Ana I. Domingos
• Keywords: Diphtheria Toxin; Catecholaminergic cell groups

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