Single nucleus RNA-seq analysis of two-month old Csf1r+/- mouse brains

Dominant inactivating mutations in the colony stimulating factor-1 receptor (CSF1R) cause an adult-onset neurodegenerative disease associated with white matter loss and axonal degeneration designated CSF-1R related leukoencephalopathy (CRL), that is modeled in the Csf1r+/- mouse. CRL is caused by microglial dysfunction. However, the primary microglial deficit, caused by insufficient CSF-1R signaling, is unknown. To address this question, we employed single-nucleus RNA sequencing of brains from young Csf1r+/- mice without pathological or behavioral alterations. Reduction of CSF-1R signaling caused defects in mitochondrial function and metal ion homeostasis in brain macrophages, with concomitant activation of cell death and stress response pathways in oligodendrocytes and neuronal subpopulations. Overall design: To investigate how reduced CSF-1R signaling impacts microglia function and their communication with other brain cells, we performed single nuclei RNA-seq (snRNA-seq) of brains isolated from 2-month-old asymptomatic Csf1r+/- mice and wild-type (wt) controls (2 mice per genotype) .