REVIEW

Microglia and early braindevelopment: An intimate journeyMorgane S. Thion1*, Florent Ginhoux2,3, Sonia Garel1*

Cross-talk between the nervous and immune systems has been well described in thecontext of adult physiology and disease. Recent advances in our understanding of immunecell ontogeny have revealed a notable interplay between neurons and microglia duringthe prenatal and postnatal emergence of functional circuits. This Review focuses onthe brain, where the early symbiotic relationship between microglia and neuronalcells critically regulates wiring, contributes to sex-specific differences in neural circuits,and relays crucial information from the periphery, including signals derived from themicrobiota. These observations underscore the importance of studying neurodevelopmentas part of a broader framework that considers nervous system interactions with microgliain a whole-body context.

The standard classification of central ner-vous system (CNS) lineages separates neu-rons that process information from glialcells, which support and modulate neuro-nal activity. Glial cells are now beginning

to emerge as major contributors to CNS devel-opment and homeostasis. In particular, brain-resident macrophages termed “microglia” appearto play major roles at the interface between theimmune and nervous systems (1–5), each of whichis crucial for host perception of the external en-vironment. Both the nervous and immune sys-tems share a number of key attributes, includingthe need for a critical training period during

which baseline levels of input are defined, suchthat subsequent atypical and potentially danger-ous signals can be detected efficiently. Despitethese common features, the nervous and immunesystems have classically been studied indepen-dently. However, there is now increasing evidenceof a strong neuroimmune interplay in adults thatdetermines how the brain modulates tissue im-munity and normal processes of aging, as wellas inflammation and neurological disorders in-cluding Alzheimer’s disease, Parkinson’s disease,multiple sclerosis, and various autoimmune pa-thologies (1–4). In addition, activation of the im-mune system during pregnancy or early life hasbeen shown to exert long-term effects on the wiringof neural circuits and may contribute to the eti-ology of neurodevelopmental disorders. Microg-lia develop in close proximity to neurons andother glial cells from early embryonic stages, andmultiple studies have now established a pivotalrole for these cells in CNS development and ho-meostasis. This Review attempts to highlight im-portant recent advances in this field, focusing on

the developmental roles of microglia at the inter-face between brain circuits and the periphery whilealso identifying key goals for future research.

Ontogeny and developmentaltrajectories of CNS immune cells

Microglia represent 5 to 15% of adult brain cells,with densities varying between distinct brainregions. They constitute by far the largest pop-ulation of immune cells in the brain, and underphysiological conditions they are unique in beinglocated within the brain parenchyma, wherethey lie in direct contact with neural progenitors,neurons, and other glial cells (namely astrocytesand oligodendrocytes). The genesis of microgliaremained obscure for many years, until land-mark studies in mammals identified a very earlyembryonic origin for this population withinthe yolk sac (YS) (1, 2, 5). This earliest primitivewave of hematopoiesis arises at embryonic day(E) 7.5 in mice, generating nucleated red bloodcells and macrophages that colonize the entireembryo. Macrophages start to enter the CNSat E9 by using the blood vasculature before clo-sure of the blood-brain barrier (BBB), which oc-curs around E13 in mice, restricting access toimmune cells that arise later in development(5) (Fig. 1). At these early stages, neural proge-nitors are actively dividing and generate the firstneurons, whereas they will give rise to oligoden-drocytes and astrocytes only at late embryonictime points. Consequently, microglia constitutethe main glial population during a large part offetal life.In most tissues located outside of the CNS, YS-

derived macrophages are progressively replen-ished from circulating monocytes, which aregenerated later in development from fetal anddefinitive bone-marrow hematopoiesis (1, 2, 5).In contrast, microglia, which are located behindthe BBB, self-renew for the entire life of the ani-mal, at least under steady-state conditions. Itis important to note that this situation is dif-ferent in zebrafish, in which secondary wavesof hematopoiesis contribute to the microglialpool. YS-derived macrophages also colonizethe meninges and other surrounding CNS tis-sues to produce border-associated macrophages(BAMs), including meningeal, choroid plexus,and perivascular macrophages (PVMs) (6) (Fig. 1).However, future studies will be needed to de-termine whether these arise from commonprecursors, with the goal of characterizing theirpotential differentiation pathways and divergentfunctions. In other words, it remains unclearwhether microglia versus BAM lineage commit-ment depends on specific precursor populationsgenerated in the YS or whether these distinctfates are instructed by local cues encounteredby macrophages as they travel through the de-veloping CNS. In contrast, choroid plexus macro-phages are known to be replaced over time bycells generated during adulthood, supportingthe notion that the choroid plexus lacks a dis-cernable BBB and thus remains accessible tocirculating bone marrow–derived cells duringlater life (6).

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1Institut de Biologie de l’École Normale Supérieure (IBENS),École Normale Supérieure, CNRS, INSERM, PSL Université Paris,75005 Paris, France. 2Singapore Immunology Network (SIgN),Agency for Science, Technology and Research (A*STAR), 8ABiomedical Grove, IMMUNOS Building no. 3-4, BIOPOLIS,138648, Singapore. 3Shanghai Institute of Immunology, ShanghaiJiaoTong University School of Medicine, 280 South ChongqingRoad, Shanghai 200025, China.*Corresponding author. Email: thion@biologie.ens.fr (M.S.T.);garel@biologie.ens.fr (S.G.)

Coronal section of the embryonic mouse somatosensory neocortex. Green, microglia; red, inhibitoryinterneurons; blue, nuclear staining.

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In adult mice, other immune populations in-cluding monocytes and lymphocytes, which lieoutside of the parenchyma, have been shown toregulate neural function via the production oflong-range signals, including interleukin-4 (IL-4),tumor necrosis factor–a (TNF-a), and interferon-g(IFNg) (7–9). However, there are only a few studiesto suggest that equivalent populations influencethe developing brain. In parallel, recent evidencehas shown that the neonatal mouse parenchymacan be infiltrated by B cells even in physiolog-ical conditions, with implications for oligoden-drogenesis (10). Future studies will thereforebe essential to decipher the potential impact ofdifferent immune cell populations on brain de-velopment, whether acting indirectly via effectson microglia or capable of directly influencingneurons.In any event, the developing CNS clearly has

a distinctive immune status associated with thepresence of long-lived resident macrophages thatoriginate in early embryogenesis (Fig. 1). Thesedata indicate that the microglial population hasa lifelong history, potential memory of previousinteractions, and a peculiar symbiotic relation-ship with the developing brain.

Neural cues and systemic signals shapemicroglial development

Colonization of the brain parenchyma by YS-derived macrophages is a long-lasting processthat spans embryogenesis and early postnatalstages (1, 11, 12). In the mouse, the first macro-phages enter around E9, and the adult patternof homogeneous tiling is reached during the sec-ond postnatal week (1), paralleling the acquisi-tion of a progressively more ramified microglialmorphology. Transcriptomic and functional studieshave revealed that, like other tissue-resident mac-rophages, microglia undergo distinct phases ofdifferentiation (13–16) that rely on signals de-rived from the maturing CNS. These signals in-clude but are not restricted to colony-stimulatingfactor 1 (CSF1), IL-34, and transforming growthfactor–b (TGF-b) (1) (Fig. 2). At the molecular

level, transition between a brain macrophagesignature and a microglial profile can be iden-tified by the expression of core genes, includ-ing genes encoding the key transcription factorSALL1 and purinergic receptor P2Y12 (1, 15, 16).Deciphering the full range of signals that regulatethis maturation process is extremely challeng-ing, given that microglia rapidly lose transcrip-tional and epigenetic identity upon separationfrom their niche (15, 16). In addition, the adultCNS environment is not sufficient to inducefull microglial differentiation of bone marrow–derived monocytic cells (17, 18), indicating thatboth their early origin and interactions with theCNS are critical for the acquisition of a bonafide microglial identity.In addition, local neural signals likely regu-

late the brain colonization pattern and hetero-geneity of microglial populations in both timeand space. Microglia enter the CNS via sequen-tial waves (11, 12) and transiently show a stereo-typical and heterogeneous pattern of localization(11, 19, 20). For instance, microglia undergo time-ly invasion into the deep layers of the neocortex,but they also associate with distinct axonal tracts,including the corpus callosum and dopaminergicmidbrain axons, and populate specific nichesknown to contain neurogenic progenitors (20).This distinctive pattern is thought to be regulatedby transient CNS cell expression of cues includ-ing IL-34, CSF1, CXCL12, and CX3CL1 (also knownas fractalkine) (1) (Fig. 2). In addition, studies inzebrafish have indicated that developmentalprogrammed cell death in the CNS regulatesmicroglial colonization (1). Following early colo-nization, there is increasing evidence that adultmicroglia display some heterogeneity acrossbrain regions, particularly in the corpus callosum,prefrontal cortex, cerebellum, or basal ganglia(1, 12, 21, 22). Indeed, transcriptomic profiling,genetic labeling, and analysis of cell dynamicshave revealed a degree of heterogeneity suggest-ing that regional differences may arise, in part,because of local signals produced by neural cells(1, 12, 21, 22). Future single-cell transcriptomic

studies will be required to unravel this heteroge-neity and determine the underlying mechanisms.Nevertheless, the studies conducted to date in-dicate that CNS-derived signals have a major roleto play in the specification, maturation, and col-onization of microglial populations (Fig. 2).In addition to local cues, the developmental

trajectory of microglia is known to be influencedby sexual identity and systemic signals such asthose derived from the microbiota or inflamma-tion at pre- and postnatal stages (14, 23). Severalreports have highlighted a distinct transcriptomicsignature of microglia in males versus female ani-mals that begins postnatally and is maintainedin adults (14, 23, 24). This sexual dimorphism ap-pears to be conserved after grafting and may oc-cur independently of circulating sex hormones,suggesting long-lasting programming by early-life hormones or genetic factors (24). Barrierorgans, including the gut, skin, and lungs, arealso populated by a diverse range of bacteriaand other microorganisms termed the “micro-biota,” which play essential roles in the develop-ment and training of both innate and adaptiveimmune systems (25). Despite their relative iso-lation behind the BBB, microglia are able torespond to microbiota-derived signals both pre-and postnatally (13, 14, 26), as germ-free micedisplay incomplete development of microgliaboth during embryogenesis and at birth (13, 14).Whereas in adults the microbiota has been shownto act on microglia in part via systemic produc-tion of short-chain fatty acids (26), the mecha-nisms involved remain unexplored in embryos.Conversely, inflammation is also known to changemicroglial developmental trajectory, from earlyembryonic stages (13, 23) into adulthood, inparticular via the production of cytokines thatcan act over long distances. Microglial responsesto inflammation and microbiota-derived signalsdiffer between females and males (14), althoughthe underlying mechanisms remain to be defined.As the list of signals that can influence microg-lial development continues to expand, it becomesincreasingly clear that these cells are capable

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Early embryogenesis Late embryogenesis

Yolk sac Progenitors CNS parenchyma

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Fig. 1. Parallel development of neural and immune cells of the CNS. Schematic showing early CNS colonization by YS-derived macrophages thatgive rise to microglia and BAMs, whereas neural progenitors generate neurons (left). At later embryonic stages (right), neural progenitors additionallyproduce oligodendrocytes and astrocytes in the parenchyma while the microglia undergo local differentiation.

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of integrating a diverse range of systemic andlocal cues that likely have important implica-tions for neuronal function.At a mechanistic level, it will be essential for

future studies to determine how microglia canintegrate such a wide variety of influences. Recentanalyses of conditional HDAC1 and -2 mutantshave shown that embryonic epigenetic modifi-cations are essential for full microglial differen-tiation (27). Because the microglial populationself-renews throughout life, somatic mutationsoccurring in the lineage or epigenetic modifica-tions within this population, induced either bylocal or systemic signals, could have major phys-iological or even pathological consequencesin adults (15, 16, 28). For instance, somatic mu-tations in primitive hemato-poiesis in mice were shown toinduce neurodegeneration inadults (28). It will therefore beimportant to assess whetherand how genetic and epigenet-ic changes during the criticaldevelopmental period regulatethe emergence of correctly tunedmicroglia and brain-resident im-mune cells.

The multifaceted rolesof microglia in earlyCNS development

Although the overall morpho-genesis of brain structures andtheir assembly do not requiremicroglia, a number of recentstudies have reported a centralrole for these cells in specificaspects of brain development,homeostasis, anddisease. Inpar-ticular, microglia were shownto eliminate apoptotic cell de-bris and contribute to activity-dependent syn-aptic reorganization, with a role in presynapticnibbling and promotion of postsynaptic spineformation (2–4, 29, 30). This later process has al-readybeen the focus of landmark reviews (1–4) andis regulated by the complement cascade, TREM2(31), or the CX3CL1-CX3CR1 receptor pathway, de-pending on the stage and structure concerned.Interestingly, these studies link microglia dys-function with behavioral deficits in adults aswell as neuropsychiatric disorders.Consistent with their distinctive early ontog-

eny and uneven pattern of brain colonization,several additional functions of microglia duringneuronal development are now beginning toemerge (Fig. 3). Microglia have been linked withthe regulation of neuronal numbers, the earlywiring of neural circuits, and the acquisition ofsex-specific features. Indeed, microglia show aprecise localization to several neurogenic nichesin the rat brain, including the postnatal subven-tricular zone and neocortex, where they regulatenonapical progenitor cell numbers via selectiveengulfment (Fig. 3A) (20). This situation has alsobeen observed in the mouse but appears lesspronounced, suggesting that these events may

display species specificity (1). In addition, microg-lia are also emerging as regulators of early cir-cuit assembly via the CX3CL1-CX3CR1 pathway.In normal physiology, microglia transiently as-sociate with specific axonal tracts, includingdopaminergic axons and corpus callosum axons,where they then regulate axon progression andfasciculation (Fig. 3B) (19, 32). Microglia canalso regulate the migration of inhibitory cor-tical interneurons, which are essential regu-lators of the excitation-inhibition balance andhave been implicated in autism spectrum dis-orders (ASDs) and schizophrenia (Fig. 3C) (19).Independently of this early role in wiring, a sub-set of white matter microglia have been reportedto promote survival of layer V pyramidal neu-

rons via the production of insulin-like growthfactor 1 (IGF-1) (Fig. 3D) (33), thus supportingthe idea that microglia can influence neuronalnumbers at distinct steps and through multi-ple mechanisms. In addition, early postnatal mi-croglia have also been reported to contributeto masculinization of the preoptic area, releas-ing prostaglandins and regulating connectiv-ity, thereby inducing male-specific copulatorybehavior in the offspring (Fig. 3E) (34). Thesefindings reveal a noteworthy interplay betweensteroid hormones, microglia, and the early ac-quisition of sexually dimorphic brain circuitryand behavior. Whether these features also applyto other brain regions or time periods such asadolescence remains entirely unknown.In parallel with their roles in early neuronal

development, microglia cross-talk with other glialcells that modulate neuronal function. Microgliahave been reported to lie in close apposition withblood vessels and to modulate endothelial tipcell fusion (1). Because microglia and PVMs aredifficult to discriminate at these early stages,further experiments will be required to clearlyassess the relative contributions of each popu-lation. In addition, microglia are key regulators

of oligodendrocyte precursor differentiation andmyelin formation. In particular, subsets of mi-croglia expressing CD11c promote myelinationvia IGF-1 release, revealing a substantial coordi-nation of both neuronal survival and myelinationby a single soluble factor (Fig. 3D) (21, 22). Lastly,astrocyte-derived IL-33 was recently shown toregulate microglial phagocytosis of neuronalspines (Fig. 3E) (35), clearly demonstrating a neu-ronal output to astrocyte-microglial interactions.Together, these studies establish microglia as

central mediators of cross-talk between neuro-nal and glial cells, where they regulate multipleaspects of early brain wiring in addition to theirwell-characterized roles in synaptic remodeling.Importantly, though specific molecular pathways

control microglial activity andlive imaging studies have re-vealed dynamic physical interac-tions with their CNS neighbors,we still have a limited under-standing of how microglia actand exert specific functions. Com-bining in vivo imaging, single-cellspatial information, and identi-fication of the key molecules in-volved via transcriptomic studieswill bridge the gap between themolecular and cellular levels andprovide a much-needed concep-tual framework for microglialfunctions.

Impact of inflammationon microglial andCNS development

In addition to local interactionsbetween microglia and theirCNS neighbors, long-range sig-naling from other embryonictissues and even the maternal

environment can modulate directly or indirectlydeveloping CNS cells. For example, it is now wellrecognized that systemic inflammation duringpregnancy is associated with defective brainwiring. Epidemiological studies have revealedpotential links between bacterial or viral infec-tion during the first and second trimesters withan increased risk of ASDs or schizophrenia inthe offspring (36). Importantly, animal modelsof this maternal immune activation (MIA) canbe induced by injections of polyI:C (a syntheticanalog of double-stranded RNA present in someviruses) or lipopolysaccharide (a component ofthe membrane of Gram-negative bacteria) inpregnant dams to respectively mimic viral orbacterial infections. These procedures are suffi-cient to induce a set of core behavioral deficitsrelated to neurodevelopmental disorders in theadult offspring (36, 37). It is important to notethat there are multiple MIA models describedin the literature that employ different stimuli andinjection protocols (dose, timing, and frequency)to induce distinct behavioral alterations. In thewell-studied MIA-polyI:C model, the Pattersonlab performed seminal work demonstrating anessential role for long-range signaling by IL-6

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Microglia

Neuron

Astrocyte

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P2Y12SALL1

TMEM119

Fractalkine/CX3CL1CD200

CSF1Cytokines (TGF-β, IL-33)

NeurotransmittersNeurotrophic factors

CX3CR1CD200RCSF1RCytokinesChemokines Neurotrophic factors

Fig. 2. Cross-talk in the development of microglia and CNS cells. Expression ofsecreted or membrane-bound factors (boxes) is essential for neuroimmunedialogue and is instrumental in the acquisition of a microglia-specific signature,as characterized by expression of CSF1R, Sall1, P2Y12, and Tmem119.

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cytokine in MIA pathology (37). More recently,it was shown that IL-6–induced differentiationof maternal T helper 17 (TH17) cells and subse-quent production of IL-17 in the mother can sig-nal directly to the placenta and embryo (38, 39).These two cytokines in particular appear to playkey roles in mediating the deleterious effectsof prenatal inflammation on embryonic wiring

of the mouse brain. In humans, levels of IL-6 pro-duction in pregnant mothers have been cor-related with functional connectivity and workingmemory in babies (40), suggesting a potentialconservation of this mechanism between species.How might circulating cytokines affect fetal

brain wiring? Although it has been proposedthat IL-17 could act directly on neurons (39), it is

also well established that microglia are per-turbed by MIA and could thereby contributeto neuronal dysfunction (3, 13, 23, 36). A consist-ent finding is that MIA models and embryonic-stage depletion of microglia induce phenotypicsimilarities in the affected animals, in particularthe distinctive dysregulation of cortical inhibi-tory interneurons (19), which is a hallmark of

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Neuronal cell survival & oligodendrogenesis

Presysnaptic pruning

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Pro-apoptotic factorsNGF, ROS, TNF

PhagocytosisE4 Chick retinal cells

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pre

Fig. 3. Main cellular functions of embryonic and postnatal microglia.Schematic representation of microglial functions during pre- and postnataldevelopment. (A) Microglia act as regulators of neuronal cell number byactively phagocytosing progenitor cells and promoting apoptosis ofdifferentiated cells via mechanisms including nerve growth factor (NGF)secretion. ROS, reactive oxygen species. (B) During pre- and postnataldevelopment, microglia also participate in the emergence of connectivityby promoting outgrowth or fasciculation of axonal tracts such asdopaminergic and corpus callosum axons. (C) Microglia can furtherinfluence neuronal migratory processes and regulate the development ofinhibitory interneurons in the embryonic somatosensory cortex. MZ,marginal zone; CP, cortical plate; IZ, intermediate zone. (D) During the firstpostnatal week, microglial release of IGF-1 is required to regulate layer Vpyramidal cell survival in the somatosensory cortex. Similarly, in thecerebellar white matter and corpus callosum of rodents, a neonatal

subpopulation of CD11chigh microglia expresses large amounts of IGF-1 andthereby regulates oligodendrocyte precursors and myelination. OPC,oligodendrocyte progenitor cell. (E) After birth, microglia are additionallyinvolved in the promotion of excitatory synapses in the neocortex, either bypromoting the formation of spines or regulating synaptic transmission.Microglia are well-described mediators of synapse elimination throughengulfment of presynaptic inputs, which rely on activity-dependent andcomplement tagging in the visual cortex and retinogeniculate system, aswell as on CX3CR1 expression in the hippocampus. This role of microglia insynaptic pruning is closely regulated by neuronal activity and by astrocytesecretion of IL-33, as recently shown in the spinal cord and thalamus.Throughout the figure, microglia are depicted in green, released factors inred, and targets in purple. For each panel, the developmental stage[embryonic (E) or postnatal (P)] and anatomical location are indicated.PGE2, prostaglandin E2; BDNF, brain-derived neurotrophic factor.

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several neurodevelopmental disorders. In addi-tion, MIA is known to induce long-term changesin the developmental trajectories of microglia(23). Because microglia are a long-lived popu-lation, early-life inflammatory events inducenot only acute effects but potentially also long-term modifications in brain wiring, plasticity,and neurodegeneration (27). Mechanistically,it will be essential to assess the roles of epige-netic modifications, which regulate microglialdifferentiation and are susceptible to environ-mental signals (13, 14).It is important to note here that maternal TH17

cells are known to be regulated by the compo-sition of the microbiota, and hence MIA-inducedmorphological and behavioral phenotypes arehighly variable between offspring generated un-der different housing conditions. Indeed, hostTH17 cells appear strictly dependent on the pres-ence of species including segmented filamen-tous bacteria (SFB) within the gut microbiota,but SFB are not present in all animal facilitiesused to generate MIA mouse models. These resultshighlight the urgent need to clarify the effects ofvarious different MIA protocols, including thenature and timing of the microbial stimulus em-ployed, the mouse strain used, and the microbiotacomposition in different animals. They further-more reveal the tight circular relationship be-tween microbiota composition, systemic immuneresponse, and brain miswiring.

Future directions

The study of neuron-microglia interactions hasled to substantial progress in our understandingof synaptic homeostasis and has major implica-tions for knowledge of the aging process andneurodegenerative diseases (1–3, 5). Additionalkey functions of microglia are emerging duringearly neurodevelopment, albeit the underlin-ing mechanisms and their direct contributionto neurodevelopmental disorders remain to befully explored. Building novel tools and modelsto dissect these functions and assess their roles

in neurodevelopmental disorders remains a ma-jor goal for the field. In particular, combining invivo studies in animal models, brain organoids,induced pluripotent stem cell–derived microglia(1), and CRISPR-CAS9 gene editing technologywill be instrumental for our comprehension ofmicroglia-neuron-glia cross-talk in physiologicaland pathological conditions. Furthermore, de-ciphering the roles of microglia versus other im-mune populations lying inside and outside theparenchyma during CNS development will beimportant to grasp the logic of neuroimmuneinteractions and the deleterious effects of in-flammation. Finally, whereas most prior studieshave focused on the prenatal or early postnatalstages of life, little is known about neuroimmuneinteractions during adolescence, which consti-tutes a major period of brain circuit rearrange-ments and a critical window of susceptibility todisorders, including schizophrenia. In light of thesexually dimorphic properties of immune cellsand their potential to modulate brain wiring, itwill be of particular interest to study this keydevelopmental event. Not only do early neuro-immune interactions forge circuits in the contextof the whole body, sexual identity, and dialoguewith the environment, they also program im-mune cells that persist in the brain throughoutlife. Defining the cellular and molecular basis ofthese interactions will be essential to advanceour current understanding of brain homeostasisand pathology.

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ACKNOWLEDGMENTS

We thank members of the Garel laboratory for stimulatingdiscussions. N. McCarthy of Insight Editing London assisted withmanuscript preparation. We apologize to those whose articlesare not cited in this Review because of space constraints. Funding:S.G.’s laboratory is supported by INSERM, CNRS, Investissementsd’Avenir (ANR-10-LABX-54 MEMO LIFE, ANR-11-IDEX-0001-02PSL* Research University) and the ERC Consolidator NImO 616080.S.G. is part of the École des Neurosciences de Paris Île-de-Francenetwork. F.G. is an EMBO YIP awardee and is supported bySingapore Immunology Network (SIgN) core funding, as well asSingapore National Research Foundation Senior Investigatorship(NRFI) NRF2016NRF-NRFI001-02. Competing interests: Nonedeclared.

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Microglia and early brain development: An intimate journeyMorgane S. Thion, Florent Ginhoux and Sonia Garel

DOI: 10.1126/science.aat0474 (6411), 185-189.362Science 

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