Distinct phases of adult microglia proliferation: a Myc-mediated early phase and a Tnfaip3-mediated late phase

Abstract

Microgliosis is a hallmark of many neurological diseases, including Alzheimer’s disease, stroke, seizure, traumatic brain and spinal cord injuries, and peripheral and optic nerve injuries. Recent studies have shown that the newly self-renewed microglia have specific neurological functions. However, the mechanism of adult microglia proliferation remains largely unclear. Here, with single-cell RNA sequencing, flow cytometry, and immunohistochemistry, we demonstrate that the sciatic nerve injury induced two distinct phases of microglia proliferation in mouse spinal cord, each with different gene expression profiles. We demonstrate that the transcription factor Myc was transiently upregulated in spinal cord microglia after nerve injury to mediate an early phase microglia proliferation. On the other hand, we reveal that the tumor-necrosis factor alpha-induced protein 3 (Tnfaip3) was downregulated to mediate the Myc-independent late-phase microglia proliferation. We show that cyclin dependent kinase 1, a kinase with important function in the M phase of the cell cycle, was involved only in the early phase. We reveal that although the early phase was neither necessary nor sufficient for the late phase proliferation, the late-phase suppressed the early phase microglia proliferation in the spinal cord. Finally, we demonstrate that the termination of spinal cord microglia proliferation required both Myc and Tnfaip3 to resume their baseline expression. Thus, we have delineated an interactive signaling network in the proliferation of differentiated microglia.

Six mitophagy-related hub genes as peripheral blood biomarkers of Alzheimer’s disease and their immune cell infiltration correlation

“…Its amplification is often observed in human tumors, and many drugs targeting the MYC pathway can be used for the treatment of tumors; the therapeutic effect might be related to the ability to restore the immune response ( Casey et al, 2018 ). In addition, MYC expression is temporarily upregulated in spinal microglia as a TF after nerve injury to mediate early-phase proliferation of microglia, which is recognized as a hallmark of AD ( Tan et al, 2022 ). The above indirectly reveals the possibility that MYC may participate in AD, but the diagnostic value of MYC in our research results needs to be further verified.…”

Long-term optical imaging of the spinal cord in awake, behaving animals

“…In the context of pain, spinal cord microglia undergo a number of transcriptomic and morphological changes in addition to proliferation (Guan et al, 2016;Ji et al, 2019;Donnelly et al, 2020). With our new preparation, we conducted long-term imaging of microglia using CX3CR1-EYFP mice (Parkhurst et al, 2013;Tan et al, 2022) and monitored changes before and after inducing neuropathic pain using the partial sciatic nerve injury (SNI) model (Shields et al, 2003;Corder et al, 2019) (Fig. 6a).…”

New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease

“…Microglia have the capacity to maintain population numbers by local self-renewal, a proliferation process independent of recruitment, allowing them to repopulate the CNS within 1 week of depletion [ 25 ]. Expression of the colony-stimulating factor 1 receptor (CSF1R) is critical for microglial development and maintenance.…”

“…IL-34 is produced by neurons, while CSF1 is primarily secreted by oligodendrocytes and astrocytes. Intriguingly, matured microglia in different brain regions exhibit regional distinction in density, function, and molecular markers [ 25 , 26 ]. The physiological significance of this spatial difference remains uncertain [ 27 , 28 ].…”