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A brain-sparing diphtheria toxin for chemical genetic ablation of peripheral cell lineages
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Orientador(es)
Resumo(s)
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.
Descrição
Palavras-chave
Chemical modification Molecular neuroscience Neuroimmunology Peripheral nervous system
Contexto Educativo
Citação
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).
Editora
Nature Publishing Group