Embryonic microglia derive from primitive macrophages and are replaced by cmyb-dependent definitive microglia in zebrafish

Giuliano Ferrero,Julien Bertrand,Catherine Robin,Elodie Di Ruggiero,Eleonore Dupuis,Magali Miserocchi,David Traver,Chris Mahony,Laurent Yvernogeau,Marianne Caron,Valerie Wittamer

doi:10.3389/conf.fnins.2019.96.00078

Abstract

Microglia, the tissue-resident macrophages of the CNS, represent major targets for therapeutic intervention in a wide variety of neurological disorders. Efficient reprogramming protocols to generate microglia-like cells in vitro using patient-derived induced pluripotent stem cells will, however, require a precise understanding of the cellular and molecular events that instruct microglial cell fates. This remains a challenge since the developmental origin of microglia during embryogenesis is controversial. Here, using genetic tracing in zebrafish, we uncover primitive macrophages as the unique source of embryonic microglia. We also demonstrate that this initial population is transient, with primitive microglia later replaced by definitive microglia that persist throughout adulthood. The adult wave originates from cmyb-dependent hematopoietic stem cells. Collectively, our work challenges the prevailing model establishing erythro-myeloid progenitors as the sole and direct microglial precursor and provides further support for the existence of multiple waves of microglia, which originate from distinct hematopoietic precursors.

Highlights

Microglia (MG) represent a distinct population of mononuclear phagocytes that serve multiple functions in central nervous system (CNS) physiology and disease (Colonna and Butovsky, 2017; Wolf et al, 2017)
Two cell populations could be discriminated in the brain based on cd45:DsRed expression (Figure 1B). qPCR analyses indicated that cd45lowmhc2+ cells expressed high levels of the MG-specific genes apolipoprotein Eb and purinergic receptor p2y12 (p2ry12) (Butovsky et al, 2014), and low levels of macrophage-expressed gene 1, a MF-specific marker (Ellett et al, 2011) (Figure 1C)
We previously identified erythro-myeloid progenitors (EMPs), oligopotent progenitors endowed with erythroid and myeloid potential that arise from the posterior blood island (PBI), in zebrafish (Bertrand et al, 2007)

Summary

Introduction

Microglia (MG) represent a distinct population of mononuclear phagocytes that serve multiple functions in central nervous system (CNS) physiology and disease (Colonna and Butovsky, 2017; Wolf et al, 2017). Elegant live-imaging studies in mouse (Davalos et al, 2005; Nimmerjahn et al, 2005) and zebrafish (Li et al, 2012; Peri and Nu€sslein-Volhard, 2008; Sieger et al, 2012) have shown that MG constantly survey their surroundings through highly motile cellular processes and quickly react to pathological stimuli by adopting morphological changes and stimulusdependent phenotypes (Ransohoff and Cardona, 2010) In addition to their role as immune effectors, MG perform numerous key functions in the development and homeostasis of the CNS, including removal of cellular debris from apoptotic neurons, production of trophic factors, synaptogenesis, and injury repair. Understanding the precise developmental program of MG has become a major goal of the field, as it will advance current reprogramming protocols for generation of MG-like cells in vitro for therapeutic use or to model disease in a dish

Results

Discussion

Conclusion