Development of ramified microglia from early macrophages in the zebrafish optic tectum.
Microglia, the resident macrophage precursors of the brain, are necessary for the maintenance of tissue homeostasis and activated by a wide range of pathological stimuli. They have a key role in immune and inflammatory responses. Early microglia stem from primitive macrophages, however the transition from early motile forms to the ramified mature resident microglia has not been assayed in real time. In order to provide such an assay, we used zebrafish transgenic lines in which fluorescent reporter expression is driven by the promoter of macrophage expressed gene 1 (mpeg1; Ellet et al. [2011]: Blood 117(4): e49-e56,). This enabled the investigation of the development of these cells in live, intact larvae. We show that microglia develop from highly motile amoeboid cells that are engaged in phagocytosis of apoptotic cell bodies into a microglial cell type that rapidly morphs back and forth between amoeboid and ramified morphologies. These morphing microglia eventually settle into a typical mature ramified morphology. Developing microglia frequently come into contact with blood capillaries in the brain, and also frequently contact each other. Up to 10 days postfertilization, microglia were observed to undergo symmetric division. In the adult optic tectum, the microglia are highly branched, resembling mammalian microglia. In addition, the mpeg1 transgene also labeled highly branched cells in the skin overlying the optic tectum from 8-9 days postfertilization, which likely represent Langerhans cells. Thus, the development of zebrafish microglia and their cellular interactions was studied in the intact developing brain in real time and at cellular resolution.
Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 100 Mallett St., Camperdown, New South Wales 2050, Australia.
Adam J
AJ
Svahn
Manuel B
MB
Graeber
Felix
F
Ellett
Graham J
GJ
Lieschke
Silke
S
Rinkwitz
Maxwell R
MR
Bennett
Thomas S
TS
Becker
D000704:Analysis of Variance; D000818:Animals; D030801:Animals, Genetically Modified; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000166:cytology / Q000196:embryology; D002452:Cell Count; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D008164:Luminescent Proteins / Q000235:genetics; D008264:Macrophages / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D017628:Microglia / Q000502:physiology*; D018613:Microscopy, Confocal; D010586:Phagocytes / Q000502:physiology; D013477:Superior Colliculi / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D013997:Time Factors; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics; D000097573:Red Fluorescent Protein
D017304:Annexin A5; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D029961:Zebrafish Proteins; D000097573:Red Fluorescent Protein; C485184:enhanced green fluorescent protein