A Comparative Biology of Microglia Across Species

Abstract

Microglia are unique brain-resident, myeloid cells. They have received growing interest for their implication in an increasing number of neurodevelopmental, acute injury, and neurodegenerative disorders of the central nervous system (CNS). Fate-mapping studies establish microglial ontogeny from the periphery during development, while recent transcriptomic studies highlight microglial identity as distinct from other CNS cells and peripheral myeloid cells. This evidence for a unique microglial ontogeny and identity raises questions regarding their identity and functions across species. This review will examine the available evidence for microglia in invertebrate and vertebrate species to clarify similarities and differences in microglial identity, ontogeny, and physiology across species. This discussion highlights conserved and divergent microglial properties through evolution. Finally, we suggest several interesting research directions from an evolutionary perspective to adequately understand the significance of microglia emergence. A proper appreciation of microglia from this perspective could inform the development of specific therapies geared at targeting microglia in various pathologies.

Keywords: evolution; identity; invertebrates; microglia; ontogeny; vertebrates; zebrafish.

FIGURE 1

Microglial ontogeny models. (A) Mouse: Primitive hematopoiesis in the embryonic yolk sac blood islands at E7.5–E8.0 results in the formation of not just erythrocytes but also highly proliferative macrophage progenitor cells that migrate to the brain. The primitive macrophages colonizing the early developing brain at E8.5 proliferate and give rise to the brain-resident microglia population. A second wave, the transient definitive hematopoiesis in the yolk sac, gives rise to erythromyeloid progenitor cells by E8.0–E8.5 and to T- and B-lymphoid progenitor cells by E9.0. On reaching the fetal liver by E10.5, these cells undergo definitive hematopoiesis to result in the formation of all hematopoietic lineage cells, including monocytes. Recent studies now indicate that definitive hematopoiesis also partly contribute to the brain resident microglia population through hoxb8⁺ and CCR2⁺ monocyte populations taking up residence in the early developing brain parenchyma by E12.5 and E17.0, respectively. (B) Zebrafish: Embryonic microglia originating in the rostral blood islands through primitive hematopoiesis by 4 dpf migrates to and populates the embryonic brain until 15 dpf, they disappear entirely by 45 dpf. In essence, the embryonic microglia are replaced by another wave of incoming microglia that arise as a result of definitive hematopoiesis occurring in the ventral walls of the dorsal aorta beginning at 15 dpf. They are the dominant microglia population by 45 dpf and serve as adult microglia throughout the fish’s life.

FIGURE 2

Suggested future comparative studies on microglia across species. Studies describing microglia in invertebrates are sparse and usually focus on microglia seen in phyla Annelida (in leeches and earthworms) and Mollusca (in mussels). However, the ontogeny and detailed characterization of invertebrate microglia are still lacking. Contrary to this, vertebrate microglia, especially zebrafish and mammalian microglia have been extensively studied and characterized for their origin, identity, and function. Additional study of microglia in the existing invertebrate models in conjunction with expanding the search to other invertebrate species and examining them with respect to their ontogeny, identity, and function in relation to vertebrate microglia could help us gain insight on the significance of microglial emergence in evolution.