Reference : A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a do...
Scientific journals : Article
Life sciences : Genetics & genetic processes
http://hdl.handle.net/10993/51196
A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling
English
Stables, Jennifer [Mater Research Institute-University of Queensland > Translational Research Institute]
Green, Emma [University of Edinburgh > Centre for Inflammation Research and Simons Initiative for the Developing Brain]
Sehgal, Anuj [Mater Research Institute-University of Queensland > Translational Research Institute]
Patkar, Omkar [Mater Research Institute-University of Queensland > Translational Research Institute]
Keshvari, Sahar [Mater Research Institute-University of Queensland > Translational Research Institute]
Taylor, Isis [Mater Research Institute-University of Queensland > Translational Research Institute]
Ashkroft, Maisie [University of Edinburgh > Centre for Inflammation Research and Simons Initiative for the Developing Brain]
Grabert, Kathleen [Karolinska Institutet > Toxicology Unit, Institute of Environmental Medicine]
Wollscheid-Lengeling, Evi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core >]
Szymkowiak, Stefan [University of Edinburgh > UK Dementia Research Institute, Centre for Discovery Brain Sciences]
McColl, Barry [University of Edinburgh > UK Dementia Research Institute, Centre for Discovery Brain Sciences]
Adamson, Antony [University of Manchester > Genome Editing Unit, Faculty of Biology, Medicine and Health]
Humphreys, Neil [University of Manchester > Genome Editing Unit, Faculty of Biology, Medicine and Health]
Mueller, Werner [University of Manchester > Genome Editing Unit, Faculty of Biology, Medicine and Health]
Starobova, Hana [University of Queensland > Institute for Molecular Biosciences & School of Pharmacy]
Vetter, Irinia [University of Queensland > Institute for Molecular Biosciences & School of Pharmacy]
Shabestari, Sepideh Kiani [University of California > Department of Neurobiology & Behavior,]
Blurton-Jones, Matthew [University of California > Department of Neurobiology & Behavior,]
Summers, Kim [Mater Research Institute-University of Queensland > Translational Research Institute]
Irvine, Katharine [Mater Research Institute-University of Queensland > Translational Research Institute]
Pridans, Clare [University of Edinburgh > Centre for Inflammation Research and Simons Initiative for the Developing Brain]
Hume, David [Mater Research Institute-University of Queensland > Translational Research Institute]
15-Apr-2022
Development
149
8
Yes
International
[en] CSF1R ; Kinase-dead ; Leukoencephalopathy ; Macrophage
[en] Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.
http://hdl.handle.net/10993/51196
10.1242/dev.200237

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