Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations
| Autor: | Kim M. Summers, Clare Pridans, Stephen J. Bush, Arnauld Belmer, Sahar Keshvari, Melanie Caruso, Ngari Teakle, Omkar L. Patkar, David A. Hume, Katharine M. Irvine |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Neurogenesis Knockout Neurogenic Hippocampus DA dark agouti rat strain Biology medicine.disease_cause Article lcsh:RC321-571 ALSP adult onset leukoencephalopathy with axonal spheroids and pigmented glia Gene Knockout Techniques 03 medical and health sciences 0302 clinical medicine Leukoencephalopathy RMS rostral migratory stream medicine Animals Humans lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Csf1rko Csf1r knockout mutation Mutation Microglia Dentate gyrus Dopaminergic DG dentate gyrus PS-NCAM poly-sialylated neural cell adhesion molecule Neurodegenerative Diseases CSF1R SVZ sub-ventricular zone Phenotype Rats Cell biology Disease Models Animal 030104 developmental biology medicine.anatomical_structure nervous system Neurology Receptors Granulocyte-Macrophage Colony-Stimulating Factor Rat Female Neural cell adhesion molecule RNA-seq Haploinsufficiency 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease, Vol 151, Iss, Pp 105268-(2021) Neurobiology of Disease Patkar, O L, Caruso, M, Teakle, N, Keshvari, S, Bush, S J, Pridans, C, Belmer, A, Summers, K M, Irvine, K M & Hume, D A 2021, ' Analysis of homozygous and heterozygous Csf1r knockout in the rat as a model for understanding microglial function in brain development and the impacts of human CSF1R mutations. ', Neurobiology of disease, vol. 151, 105268 . https://doi.org/10.1016/j.nbd.2021.105268 |
| ISSN: | 0969-9961 |
| DOI: | 10.1016/j.nbd.2021.105268 |
| Popis: | Mutations in the human CSF1R gene have been associated with dominant and recessive forms of neurodegenerative disease. Here we describe the impacts of Csf1r mutation in the rat on development of the brain. Diffusion imaging indicated small reductions in major fiber tracts that may be associated in part with ventricular enlargement. RNA-seq profiling revealed a set of 105 microglial markers depleted in all brain regions of the Csf1rko rats. There was no evidence of region or sex-specific expression of microglia-associated transcripts. Other than the microglial signature, Csf1rko had no effect on any neuronal or region-specific transcript cluster. Expression of markers of oligodendrocytes, astrocytes, dopaminergic neurons and Purkinje cells was minimally affected. However, there were defects in dendritic arborization of doublecortin-positive neurogenic precursors and expression of poly-sialylated neural cell adhesion molecule (PS-NCAM) in the dentate gyrus of the hippocampus. Heterozygous Csf1rko rats had no detectable brain phenotype. We conclude that most brain developmental processes occur normally in the absence of microglia and that CSF1R haploinsufficiency is unlikely to cause leukoencephalopathy. Highlights • Csf1rko rats lack microglia but have normal brain development. • RNA-seq analysis revealed selective loss of microglia-associated transcripts. • Postnatal maturation of neurons in the dentate gyrus of the hippocampus was compromised. • There was no evidence of haploinsufficiency in young or aged heterozygous Csf1rko rats. |
| Databáze: | OpenAIRE |
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