PUBLICATION

A csf1rb mutation uncouples two waves of microglia development in zebrafish

Authors

Ferrero, G., Miserocchi, M., Di Ruggiero, E., Wittamer, V.

ID

ZDB-PUB-201212-14

Date

2020

Source

Development (Cambridge, England) 148(1): (Journal)

Registered Authors

Wittamer, Valerie

Keywords

Colony-stimulating factor 1 receptor, Development, Hematopoiesis, Macrophages, Microglia, Zebrafish

MeSH Terms

Hematopoiesis
Zebrafish Proteins/genetics*
Zebrafish Proteins/metabolism
Zebrafish/embryology
Zebrafish/genetics*
Gene Expression Regulation, Developmental
Microglia/metabolism*
Embryo, Nonmammalian/metabolism
Embryonic Development
Phagocytes/metabolism
Mutation/genetics*
Hematopoietic Stem Cells/metabolism
Aging/genetics
Protein-Tyrosine Kinases/genetics*
Protein-Tyrosine Kinases/metabolism
Receptor Protein-Tyrosine Kinases/genetics
Receptor Protein-Tyrosine Kinases/metabolism
Animals
Myeloid Cells/metabolism
Macrophages/metabolism

(all 20)

PubMed

33298459 Full text @ Development

Abstract

In vertebrates, the ontogeny of microglia, the resident macrophages of the central nervous system, initiates early during development from primitive macrophages. While murine embryonic microglia then persist through life, in zebrafish these cells are transient, as they are fully replaced by an adult population originating from larval hematopoietic stem cell (HSC)-derived progenitors. Colony-stimulating factor receptor 1 (csf1r) is a fundamental regulator of microglia ontogeny in vertebrates, including zebrafish which possess two paralogous genes: csf1ra and csf1rb While previous work showed mutation in both genes completely abrogates microglia development, the specific contribution of each paralog remains largely unknown. Here, using a fate-mapping strategy to discriminate between the two microglial waves, we uncover non-overlapping roles for csf1ra and csf1rb in hematopoiesis, and identified csf1rb as an essential regulator of adult microglia development. Notably, we demonstrate that csf1rb positively regulates HSC-derived myelopoiesis, resulting in macrophage deficiency, including microglia, in adult mutant animals. Overall, this study contributes to new insights into evolutionary aspects of Csf1r signaling and provides an unprecedented framework for the functional dissection of embryonic versus adult microglia in vivo.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
apoeb	csf1ra^j4e1/j4e1	standard conditions	Day 6		microglial cell	ISH	Fig. 3
apoeb	csf1ra^j4e1/j4e1	standard conditions	Protruding-mouth		microglial cell	ISH	Fig. 3
apoeb	csf1ra^j4e1/j4e1; csf1rb^re01/re01	standard conditions	Protruding-mouth		microglial cell	ISH	Fig. 3
apoeb	csf1ra^j4e1/j4e1; csf1rb^re01/re01	standard conditions	Day 6		microglial cell	ISH	Fig. 3
apoeb	csf1rb^re01/re01	standard conditions	Day 6		microglial cell	ISH	Fig. 3
apoeb	csf1rb^re01/re01	standard conditions	Protruding-mouth		microglial cell	ISH	Fig. 3
apoeb	WT	standard conditions	Protruding-mouth		microglial cell	ISH	Fig. 3
apoeb	WT	standard conditions	Day 6		microglial cell	ISH	Fig. 3
csf1ra	sd3Tg; sd6Tg	standard conditions	Adult		head kidney mononuclear phagocyte	RTPCR	Fig. 2
csf1ra	sd3Tg; sd6Tg	standard conditions	Adult	Not Detected	integument mononuclear phagocyte	RTPCR	Fig. 2

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
csf1ra^j4e1/j4e1	standard conditions	Prim-5	macrophage normal amount, normal	Fig. 3
csf1ra^j4e1/j4e1	standard conditions	Protruding-mouth	microglial cell apoeb expression decreased amount, abnormal	Fig. 3
csf1ra^j4e1/j4e1	standard conditions	Protruding-mouth	microglial cell decreased amount, abnormal	Fig. 3
csf1ra^j4e1/j4e1	standard conditions	Day 6	microglial cell apoeb expression decreased amount, abnormal	Fig. 3
csf1ra^j4e1/j4e1	standard conditions	Day 6	microglial cell decreased amount, abnormal	Fig. 3
csf1ra^j4e1/j4e1; csf1rb^re01/re01	standard conditions	Prim-5	macrophage normal amount, normal	Fig. 3
csf1ra^j4e1/j4e1; csf1rb^re01/re01	standard conditions	Protruding-mouth	microglial cell apoeb expression decreased amount, abnormal	Fig. 3
csf1ra^j4e1/j4e1; csf1rb^re01/re01	standard conditions	Protruding-mouth	microglial cell decreased amount, abnormal	Fig. 3
csf1ra^j4e1/j4e1; csf1rb^re01/re01	standard conditions	Day 6	microglial cell apoeb expression decreased amount, abnormal	Fig. 3
csf1ra^j4e1/j4e1; csf1rb^re01/re01	standard conditions	Day 6	microglial cell decreased amount, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
gl22Tg	Tg(mpeg1:EGFP)	Transgenic Insertion
hg1		Point Mutation	runx1
j4e1		Point Mutation	csf1ra
re01		Small Deletion	csf1rb
s898Tg	Tg(kdrl:Cre)	Transgenic Insertion
sa1503		Point Mutation	csf1rb
sd3Tg	Tg(ptprc:DsRed)	Transgenic Insertion
sd5Tg	Tg(actb2:LOXP-STOP-LOXP-DsRedEx)	Transgenic Insertion
sd6Tg	Tg(mhc2dab:EGFP)	Transgenic Insertion

1 - 9 of 9

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
csf1ra^j4e1/j4e1
csf1ra^j4e1/j4e1; csf1rb^re01/re01
csf1ra^j4e1/j4e1; csf1rb^re01/re01; gl22Tg; s898Tg; sd5Tg
csf1ra^j4e1/j4e1; gl22Tg; s898Tg; sd5Tg
csf1ra^j4e1/j4e1; gl22Tg; sd5Tg
csf1rb^re01/re01
csf1rb^re01/re01; gl22Tg; s898Tg; sd5Tg
csf1rb^re01/re01; gl22Tg; sd5Tg
csf1rb^{sa1503/sa1503}
runx1^hg1/hg1

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Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
Cre	EFG	Cre
DsRed	EFG	DsRed
DsRedx	EFG	DsRedx
EGFP	EFG	EGFP

Mapping

Ferrero et al., 2020 ZDB-PUB-201212-14 PMID:33298459

A csf1rb mutation uncouples two waves of microglia development in zebrafish

Ferrero et al., 2020

ZDB-PUB-201212-14
PMID:33298459