# Mechanism of microglia proliferation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $422,782

## Abstract

ABSTRACT
Microglia proliferation occurs in numerous neurological disorders, including peripheral and optic nerve injuries,
neurodegenerative diseases, stroke, traumatic brain and spinal cord injuries, multiple sclerosis, seizure, infection,
irradiation, and mental disorders. Parabiotic studies, along with studies with single-cell imaging and multicolor
fluorescence fate mapping system, have demonstrated that the self-renewal of resident microglia is responsible
for the expansion of microglia population in mouse models of neurological diseases. In fact, the newborn
microglia generated from microglial self-renewal have significant neurological function with unique transcriptional
profile. Moreover, dysregulation of microglia proliferation significantly impacts the development of many
neurological diseases, indicating that microglia proliferation plays critical roles in the development of neurological
diseases. However, the mechanism of microglia proliferation is largely unknown. We did a group of preliminary
experiments to explore the mechanisms of microglia proliferation, and identified a group of embryonic genes that
have similar expression pattern as proliferation marker Mki67 during microglia development. With single-cell
RNA sequencing (scRNA-Seq), we found that these embryonic microglial proliferation-associated genes were
upregulated in lumbar cord microglia around the time they proliferate. Our qRT-PCR from the sorted microglia
and microglial RiboTag confirmed the transient upregulation of transcription factor Myc, one of the embryonic
microglial proliferation-associated genes, in lumbar cord microglia shortly after sciatic nerve injury. We also found
that the deletion of Myc from adult microglia significantly prevented the early phase of nerve injury-induced
microglia proliferation, with the late phase of microglia proliferation intact, suggesting that adult microglia
proliferation has a Myc-dependent initiation phase and a Myc-independent maintenance phase. To explore the
signaling pathway upstream of microglial Myc upregulation, we analyzed our scRNA-Seq and found that the
genes encoding DAP12 and its associated membrane protein TREM2, which is required for microglia
proliferation in Alzheimer's disease, are upregulated in lumbar cord microglia after sciatic nerve injury. In addition,
we found that Syk, a protein tyrosine kinase downstream of TREM2 and DAP12, and upstream of Myc, is
phosphorylated in lumbar cord microglia shortly after sciatic nerve injury. In searching for Myc independent
mechanism for the maintenance phase of microglia proliferation, we also found that Mafb, a transcription factor
expressed at much higher level in adult than in embryonic microglia, inhibits microglia proliferation in adult but
not in neonate, and is downregulated in lumbar cord microglia after nerve injury-induced Myc upregulation. We
now propose a set of experiments to further delineate the mechanism of microglia proliferation. Aim 1: To test
the hypo...

## Key facts

- **NIH application ID:** 10185588
- **Project number:** 1R01NS121144-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Zhonghui Guan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $422,782
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185588

## Citation

> US National Institutes of Health, RePORTER application 10185588, Mechanism of microglia proliferation (1R01NS121144-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10185588. Licensed CC0.

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