A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signaling

Jennifer Stables, Emma Green, Anuj Sehgal, Omkar Patkar, Sahar Keshvari, Isis Taylor, Maisie Ashcroft, Kathleen Grabert, Evi Wollscheid-Lengeling, Stefan Szymkowiak, Barry W McColl, Antony Adamson, Neil E Humphreys, Werner Mueller, Hana Starobova, Irina Vetter, Sepideh Kiani Shabestari, Mathew Blurton-Jones, Kim Summers, Katharine M. IrvineClare Pridans, David A. Hume*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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 (Glu631Lys; 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 expands tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborization were reduced in the Csf1rE631K/+ mice as in ALSP patients. 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 disease-associated CSF1R mutations encode dominant negative repressors of CSF1R signaling. We speculate that leukoencephalopathy associated with human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.
Original languageEnglish
JournalDevelopment
DOIs
Publication statusPublished - 25 Mar 2022

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