Merck
  • Home
  • Search Results
  • Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature.

Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature.

Nature cell biology (2020-06-17)
Bilal N Sheikh, Sukanya Guhathakurta, Tsz Hong Tsang, Marius Schwabenland, Gina Renschler, Benjamin Herquel, Vivek Bhardwaj, Herbert Holz, Thomas Stehle, Olga Bondareva, Nadim Aizarani, Omar Mossad, Oliver Kretz, Wilfried Reichardt, Aindrila Chatterjee, Laura J Braun, Julien Thevenon, Herve Sartelet, Thomas Blank, Dominic Grün, Dominik von Elverfeldt, Tobias B Huber, Dietmar Vestweber, Sergiy Avilov, Marco Prinz, Joerg M Buescher, Asifa Akhtar
ABSTRACT

Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syndromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex-Mof, Kansl2 or Kansl3-unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)-NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work establishes that neurovascular function is determined by the neural metabolic environment.

MATERIALS
Product Number
Brand
Product Description

Supelco
4-Hydroxytamoxifen, analytical standard, (E) and (Z) isomers (50:50)
Sigma-Aldrich
Anti-acetyl-Histone H4 (Lys16) Antibody, Upstate®, from rabbit
Supelco
Lipid Removal Agent (LRA), pkg of 500 g
Sigma-Aldrich
2,3,4,5,6-Pentafluorobenzyl bromide, 99%
Sigma-Aldrich
Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, ≥98% (TLC), powder
Sigma-Aldrich
meso-Tetraphenylporphyrin, BioReagent, suitable for fluorescence, ≥99.0% (HPLC)
Sigma-Aldrich
Bovine Serum Albumin, fatty acid free, low endotoxin, lyophilized powder, BioReagent, suitable for cell culture, ≥96% (agarose gel electrophoresis)
Sigma-Aldrich
2-(Diisopropylamino)ethanol, ≥99%
Sigma-Aldrich
Lignoceric acid, ≥99% (GC)
Sigma-Aldrich
Poly-L-lysine solution, 0.1 % (w/v) in H2O
Sigma-Aldrich
Ribonuclease A from bovine pancreas, Type I-A, powder, ≥60% RNase A basis (SDS-PAGE), ≥50 Kunitz units/mg protein
Sigma-Aldrich
Arachidic acid, ≥99%
Sigma-Aldrich
Myristic acid, Sigma Grade, ≥99%
Sigma-Aldrich
Endothelial Cell Growth Supplement, 150mg, The Endothelial Cell Growth Supplement is designed for use as a cell culture media supplement. This cell growth supplement is available in a 150 mg format & has been optimized & validated for cell culture.