A Subpopulation of Microglia Generated in the Adult Mouse Brain Originates from Prominin-1-Expressing Progenitors

Abstract

Microglia maintain brain health and play important roles in disease and injury. Despite the known ability of microglia to proliferate, the precise nature of the population or populations capable of generating new microglia in the adult brain remains controversial. We identified Prominin-1 (Prom1; also known as CD133) as a putative cell surface marker of committed brain myeloid progenitor cells. We demonstrate that Prom1-expressing cells isolated from mixed cortical cultures will generate new microglia in vitro. To determine whether Prom1-expressing cells generate new microglia in vivo, we used tamoxifen inducible fate mapping in male and female mice. Induction of Cre recombinase activity at 10 weeks in Prom1expressing cells leads to the expression of TdTomato in all Prom1-expressing progenitors and newly generated daughter cells. We observed a population of new TdTomato-expressing microglia at 6 months of age that increased in size at 9 months. When microglia proliferation was induced using a transient ischemia/reperfusion paradigm, little proliferation from the Prom1-expressing progenitors was observed with the majority of new microglia derived from Prom1-negative cells. Together, these findings reveal that Prom1-expressing myeloid progenitor cells contribute to the generation of new microglia both in vitro and in vivo. Furthermore, these findings demonstrate the existence of an undifferentiated myeloid progenitor population in the adult mouse brain that expresses Prom1. We conclude that Prom1-expressing myeloid progenitors contribute to new microglia genesis in the uninjured brain but not in response to ischemia/reperfusion.

AR12 increases BAG3 expression which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

“…Deletion of Rubicon in the macrophages abolished the degradation of all tested proteins and the increase in eIF2α S51 phosphorylation (Supplementary Figure 1). We next determined in HCN2 neuronal cells and in BV2 microglia the abilities of AR12 and neratinib to reduce the expression of mutant forms of APP and Tau [26][27][28][29]. AR12 and the drug combination reduced the expression of Tau 301L which trended to be less than the reduction of wild type Tau (Figure 5).…”

Established and emerging techniques for the study of microglia: visualization, depletion, and fate mapping

“…Using a similar mouse model, the time course of microglial and macrophage infiltration into the various compartments of the eye was recently mapped at high spatiotemporal resolution ( Wieghofer et al, 2021 ). More recently, researchers identified prominin 1 as a marker of committed myeloid progenitors in the adult CNS under homeostatic conditions, and employed a novel fate mapping approach using Prom1 CreERT 2 :R26 tdT mice to demonstrate that Prominin-1 (Prom1) + progenitors also contribute to microglial proliferation during homeostasis ( Prater et al, 2021 ).…”