Skip to main content
SpringerLink
Log in

Microglial Ontogeny and Functions in Shaping Brain Circuits

  • Chapter
  • First Online:
Macrophages: Biology and Role in the Pathology of Diseases

  • 2537 Accesses

Abstract

Microglia are the resident macrophage population of the central nervous system (CNS). Adequate microglial function is crucial for a healthy CNS; microglia are not only the first immune sentinels of infection and inflammation, but are also involved in the maintenance of brain homeostasis. Emerging data are showing new and fundamental roles for microglia in the control of neuronal proliferation and differentiation, as well as in the formation of synaptic connections. In parallel, recent studies on microglial origin indicate that these cells arise very early during development from progenitors in the embryonic yolk sac that produce cells able to persist in the CNS into adulthood. These unique immune cells are thus present at all stages of brain development, including the prenatal stage of neuronal circuit formation, which points to the intriguing possibility that microglia might be involved in development of the CNS. Here, we review the latest advances in our understanding of the origin, differentiation, and homeostasis of microglial cells. In light of this knowledge, we then discuss the microglial contribution to CNS development and their emerging significance in the field of CNS disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10(12):1538–1543

    CAS  PubMed  Google Scholar 

  • Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14(9):1142–1149

    CAS  PubMed  Google Scholar 

  • Akiyama H, McGeer PL (1990) Brain microglia constitutively express beta-2 integrins. J Neuroimmunol 30(1):81–93

    CAS  PubMed  Google Scholar 

  • Alliot F, Lecain E, Grima B, Pessac B (1991) Microglial progenitors with a high proliferative potential in the embryonic and adult mouse brain. Proc Natl Acad Sci U S A 88(4):1541–1545

    CAS  PubMed Central  PubMed  Google Scholar 

  • Alliot F, Godin I, Pessac B (1999) Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res 117(2):145–152

    CAS  PubMed  Google Scholar 

  • Ashwell K (1990) Microglia and cell death in the developing mouse cerebellum. Brain Res Dev Brain Res 55(2):219–230

    CAS  PubMed  Google Scholar 

  • Ashwell K (1991) The distribution of microglia and cell death in the fetal rat forebrain. Brain Res Dev Brain Res 58(1):1–12

    CAS  PubMed  Google Scholar 

  • Ashwood P, Wills S, Van de Water J (2006) The immune response in autism: a new frontier for autism research. J Leukoc Biol 80(1):1–15

    CAS  PubMed  Google Scholar 

  • Bachstetter AD, Morganti JM, Jernberg J, Schlunk A, Mitchell SH, Brewster KW, Hudson CE, Cole MJ, Harrison JK, Bickford PC, Gemma C (2011) Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats. Neurobiol Aging 32(11):2030–2044

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bayer SA, Altman J (1991) Neocortical development. Raven Press, New York

    Google Scholar 

  • Bechade C, Cantaut-Belarif Y, Bessis A (2013) Microglial control of neuronal activity. Front Cell Neurosci 7:32

    PubMed Central  PubMed  Google Scholar 

  • Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103(43):16021–16026

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bertrand JY, Jalil A, Klaine M, Jung S, Cumano A, Godin I (2005) Three pathways to mature macrophages in the early mouse yolk sac. Blood 106(9):3004–3011

    CAS  PubMed  Google Scholar 

  • Bessis A, Bechade C, Bernard D, Roumier A (2007) Microglial control of neuronal death and synaptic properties. Glia 55(3):233–238

    PubMed  Google Scholar 

  • Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8(1):57–69

    CAS  PubMed  Google Scholar 

  • Brown AS (2011) The environment and susceptibility to schizophrenia. Prog Neurobiol 93(1):23–58

    CAS  PubMed Central  PubMed  Google Scholar 

  • Capotondo A, Milazzo R, Politi LS, Quattrini A, Palini A, Plati T, Merella S, Nonis A, di Serio C, Montini E, Naldini L, Biffi A (2012) Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation. Proc Natl Acad Sci U S A 109(37):15018–15023

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924

    CAS  PubMed  Google Scholar 

  • Chan WY, Kohsaka S, Rezaie P (2007) The origin and cell lineage of microglia: new concepts. Brain Res Rev 53(2):344–354

    CAS  PubMed  Google Scholar 

  • Chen SK, Tvrdik P, Peden E, Cho S, Wu S, Spangrude G, Capecchi MR (2010) Hematopoietic origin of pathological grooming in Hoxb8 mutant mice. Cell 141(5):775–785

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chew LJ, Fusar-Poli P, Schmitz T (2013) Oligodendroglial alterations and the role of microglia in white matter injury: relevance to schizophrenia. Dev Neurosci 35(2–3):102–129

    CAS  PubMed  Google Scholar 

  • Chihara T, Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, Kimura F, Okada S (2010) IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation. Cell Death Differ 17(12):1917–1927

    CAS  PubMed  Google Scholar 

  • Cuadros MA, Navascues J (2001) Early origin and colonization of the developing central nervous system by microglial precursors. Prog Brain Res 132:51–59

    CAS  PubMed  Google Scholar 

  • Cunningham CL, Martinez-Cerdeno V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci 33(10):4216–4233

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dai XM, Ryan GR, Hapel AJ, Dominguez MG, Russell RG, Kapp S, Sylvestre V, Stanley ER (2002) Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 99(1):111–120

    CAS  PubMed  Google Scholar 

  • Dalmau I, Vela JM, Gonzalez B, Finsen B, Castellano B (2003) Dynamics of microglia in the developing rat brain. J Comp Neurol 458(2):144–157

    PubMed  Google Scholar 

  • Daneman R (2012) The blood–brain barrier in health and disease. Ann Neurol 72(5):648–672

    CAS  PubMed  Google Scholar 

  • Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468(7323):562–566

    CAS  PubMed Central  PubMed  Google Scholar 

  • Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758

    CAS  PubMed  Google Scholar 

  • de Groot CJ, Huppes W, Sminia T, Kraal G, Dijkstra CD (1992) Determination of the origin and nature of brain macrophages and microglial cells in mouse central nervous system, using non-radioactive in situ hybridization and immunoperoxidase techniques. Glia 6(4):301–309

    PubMed  Google Scholar 

  • Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, Kipnis J (2012) Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484(7392):105–109

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dijkstra CD, Dopp EA, Joling P, Kraal G (1985) The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology 54(3):589–599

    CAS  PubMed Central  PubMed  Google Scholar 

  • Diserbo M, Agin A, Lamproglou I, Mauris J, Staali F, Multon E, Amourette C (2002) Blood–brain barrier permeability after gamma whole-body irradiation: an in vivo microdialysis study. Can J Physiol Pharmacol 80(7):670–678

    CAS  PubMed  Google Scholar 

  • Esiri MM, Morris CS (1991) Immunocytochemical study of macrophages and microglial cells and extracellular matrix components in human CNS disease. 2. Non-neoplastic diseases. J Neurol Sci 101(1):59–72

    CAS  PubMed  Google Scholar 

  • Fedoroff S, Zhai R, Novak JP (1997) Microglia and astroglia have a common progenitor cell. J Neurosci Res 50(3):477–486

    CAS  PubMed  Google Scholar 

  • Fujita S, Kitamura T (1975) Origin of brain macrophages and the nature of the so-called microglia. Acta Neuropathol Suppl Suppl 6:291–6

    Google Scholar 

  • Garceau V, Smith J, Paton IR, Davey M, Fares MA, Sester DP, Burt DW, Hume DA (2010) Pivotal advance: avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products. J Leukoc Biol 87(5):753–764

    CAS  PubMed  Google Scholar 

  • Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, Helft J, Chow A, Elpek KG, Gordonov S, et al (2012) Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nature immunology 13: 1118–1128

    Google Scholar 

  • Geissmann F, Jung S, Littman DR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71–82

    Google Scholar 

  • Ginhoux F, Merad M (2010) Ontogeny and homeostasis of Langerhans cells. Immunol Cell Biol 88(4):387–392

    PubMed  Google Scholar 

  • Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45

    PubMed Central  PubMed  Google Scholar 

  • Godin IE, Garcia-Porrero JA, Coutinho A, Dieterlen-Lievre F, Marcos MA (1993) Para-aortic splanchnopleura from early mouse embryos contains B1a cell progenitors. Nature 364(6432):67–70

    CAS  PubMed  Google Scholar 

  • Graeber MB (2010) Changing face of microglia. Science 330(6005):783–788

    CAS  PubMed  Google Scholar 

  • Greter M, Lelios I, Pelczar P, Hoeffel G, Price J, Leboeuf M, Kundig TM, Frei K, Ginhoux F, Merad M, Becher B (2012) Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia. Immunity 37(6):1050–1060

    CAS  PubMed  Google Scholar 

  • Guilbert LJ, Stanley ER (1980) Specific interaction of murine colony-stimulating factor with mononuclear phagocytic cells. J Cell Biol 85(1):153–159

    CAS  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394

    CAS  PubMed  Google Scholar 

  • Hao C, Richardson A, Fedoroff S (1991) Macrophage-like cells originate from neuroepithelium in culture: characterization and properties of the macrophage-like cells. Int J Dev Neurosci 9(1):1–14

    CAS  PubMed  Google Scholar 

  • Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, Becker CD, See P, Price J, Lucas D, Greter M, Mortha A, Boyer SW, Forsberg EC, Tanaka M, van Rooijen N, Garcia-Sastre A, Stanley ER, Ginhoux F, Frenette PS, Merad M (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38(4):792–804

    CAS  PubMed  Google Scholar 

  • Herbomel P, Thisse B, Thisse C (1999) Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development 126(17):3735–3745

    CAS  PubMed  Google Scholar 

  • Herbomel P, Thisse B, Thisse C (2001) Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Dev Biol 238(2):274–288

    CAS  PubMed  Google Scholar 

  • Hoeffel G, Wang Y, Greter M, See P, Teo P, Malleret B, Leboeuf M, Low D, Oller G, Almeida F, Choy SH, Grisotto M, Renia L, Conway SJ, Stanley ER, Chan JK, Ng LG, Samokhvalov IM, Merad M, Ginhoux F (2012) Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209(6):1167–1181

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E (2012) Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J Neurosci 32(43):15106–15111

    CAS  PubMed  Google Scholar 

  • Hughes V (2012) Microglia: the constant gardeners. Nature 485(7400):570–572

    CAS  PubMed  Google Scholar 

  • Hume DA, Perry VH, Gordon S (1983) Immunohistochemical localization of a macrophage-specific antigen in developing mouse retina: phagocytosis of dying neurons and differentiation of microglial cells to form a regular array in the plexiform layers. J Cell Biol 97(1):253–257

    CAS  PubMed  Google Scholar 

  • Hutchins KD, Dickson DW, Rashbaum WK, Lyman WD (1990) Localization of morphologically distinct microglial populations in the developing human fetal brain: implications for ontogeny. Brain Res Dev Brain Res 55(1):95–102

    CAS  PubMed  Google Scholar 

  • Imamoto K, Leblond CP (1978) Radioautographic investigation of gliogenesis in the corpus callosum of young rats. II. Origin of microglial cells. J Comp Neurol 180(1):139–163

    CAS  PubMed  Google Scholar 

  • Janossy G, Bofill M, Poulter LW, Rawlings E, Burford GD, Navarrete C, Ziegler A, Kelemen E (1986) Separate ontogeny of two macrophage-like accessory cell populations in the human fetus. J Immunol 136(12):4354–4361

    CAS  PubMed  Google Scholar 

  • Johnson S, Marlow N (2011) Preterm birth and childhood psychiatric disorders. Pediatr Res 69(5 Pt 2):11R–18R

    PubMed  Google Scholar 

  • Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20(11):4106–4114

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kaifu T, Nakahara J, Inui M, Mishima K, Momiyama T, Kaji M, Sugahara A, Koito H, Ujike-Asai A, Nakamura A, Kanazawa K, Tan-Takeuchi K, Iwasaki K, Yokoyama WM, Kudo A, Fujiwara M, Asou H, Takai T (2003) Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J Clin Invest 111(3):323–332

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18

    CAS  PubMed  Google Scholar 

  • Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Holscher C, Muller DN, Luckow B, Brocker T, Debowski K, Fritz G, Opdenakker G, Diefenbach A, Biber K, Heikenwalder M, Geissmann F, Rosenbauer F, Prinz M (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16(3):273–280

    CAS  PubMed  Google Scholar 

  • Kingwell K (2012) Neurodegenerative disease: microglia in early disease stages. Nat Rev Neurol 8(9):475

    PubMed  Google Scholar 

  • Kitamura T, Miyake T, Fujita S (1984) Genesis of resting microglia in the gray matter of mouse hippocampus. J Comp Neurol 226(3):421–433

    CAS  PubMed  Google Scholar 

  • Koushik SV, Wang J, Rogers R, Moskophidis D, Lambert NA, Creazzo TL, Conway SJ (2001) Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization. FASEB J 15(7):1209–1211

    CAS  PubMed  Google Scholar 

  • Kronfol Z, Remick DG (2000) Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 157(5):683–694

    CAS  PubMed  Google Scholar 

  • Kumaravelu P, Hook L, Morrison AM, Ure J, Zhao S, Zuyev S, Ansell J, Medvinsky A (2002) Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development 129(21):4891–4899

    CAS  PubMed  Google Scholar 

  • Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170

    CAS  PubMed  Google Scholar 

  • Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58(3):253–263

    PubMed  Google Scholar 

  • Leong SK, Ling EA (1992) Amoeboid and ramified microglia: their interrelationship and response to brain injury. Glia 6(1):39–47

    CAS  PubMed  Google Scholar 

  • Li Y, Liu L, Liu D, Woodward S, Barger SW, Mrak RE, Griffin WS (2004) Microglial activation by uptake of fDNA via a scavenger receptor. J Neuroimmunol 147(1–2):50–55

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li Y, Du XF, Liu CS, Wen ZL, Du JL (2012) Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev Cell 23(6):1189–1202

    CAS  PubMed  Google Scholar 

  • Lichanska AM, Hume DA (2000) Origins and functions of phagocytes in the embryo. Exp Hematol 28(6):601–611

    CAS  PubMed  Google Scholar 

  • Lichanska AM, Browne CM, Henkel GW, Murphy KM, Ostrowski MC, McKercher SR, Maki RA, Hume DA (1999) Differentiation of the mononuclear phagocyte system during mouse embryogenesis: the role of transcription factor PU.1. Blood 94(1):127–138

    CAS  PubMed  Google Scholar 

  • Lin H, Lee E, Hestir K, Leo C, Huang M, Bosch E, Halenbeck R, Wu G, Zhou A, Behrens D, Hollenbaugh D, Linnemann T, Qin M, Wong J, Chu K, Doberstein SK, Williams LT (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320(5877):807–811

    CAS  PubMed  Google Scholar 

  • Ling EA (1976) Electron-microscopic identification of amoeboid microglia in the spinal cord of newborn rats. Acta Anat (Basel) 96(4):600–609

    CAS  Google Scholar 

  • Ling EA (1979) Evidence for a haematogenous origin of some of the macrophages appearing in the spinal cord of the rat after dorsal rhizotomy. J Anat 128(Pt 1):143–154

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ling EA, Penney D, Leblond CP (1980) Use of carbon labeling to demonstrate the role of blood monocytes as precursors of the ‘ameboid cells’ present in the corpus callosum of postnatal rats. J Comp Neurol 193(3):631–657

    CAS  PubMed  Google Scholar 

  • Liu K, Waskow C, Liu X, Yao K, Hoh J, Nussenzweig M (2007) Origin of dendritic cells in peripheral lymphoid organs of mice. Nat Immunol 8(6):578–583

    CAS  PubMed  Google Scholar 

  • Mallat M, Marin-Teva JL, Cheret C (2005) Phagocytosis in the developing CNS: more than clearing the corpses. Curr Opin Neurobiol 15(1):101–107

    CAS  PubMed  Google Scholar 

  • Marin-Teva JL, Dusart I, Colin C, Gervais A, van Rooijen N, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41(4):535–547

    CAS  PubMed  Google Scholar 

  • McGrath KE, Koniski AD, Malik J, Palis J (2003) Circulation is established in a stepwise pattern in the mammalian embryo. Blood 101(5):1669–1676

    CAS  PubMed  Google Scholar 

  • McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemsz M, Feeney AJ, Wu GE, Paige CJ, Maki RA (1996) Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15(20):5647–5658

    CAS  PubMed Central  PubMed  Google Scholar 

  • Medvinsky AL, Samoylina NL, Muller AM, Dzierzak EA (1993) An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 364(6432):64–67

    CAS  PubMed  Google Scholar 

  • Mendes-Jorge L, Ramos D, Luppo M, Llombart C, Alexandre-Pires G, Nacher V, Melgarejo V, Correia M, Navarro M, Carretero A, et al (2009). Scavenger function of resident autofluorescent perivascular macrophages and their contribution to the maintenance of the blood-retinal barrier. Investigative ophthalmology & visual science 50, 5997–6005

    Google Scholar 

  • Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10(12):1544–1553

    CAS  PubMed  Google Scholar 

  • Minghetti L, Levi G (1998) Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Prog Neurobiol 54(1):99–125

    CAS  PubMed  Google Scholar 

  • Mizuno T, Doi Y, Mizoguchi H, Jin S, Noda M, Sonobe Y, Takeuchi H, Suzumura A (2011) Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-beta neurotoxicity. Am J Pathol 179(4):2016–2027

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mizutani M, Pino PA, Saederup N, Charo IF, Ransohoff RM, Cardona AE (2012) The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood. J Immunol 188(1):29–36

    CAS  PubMed Central  PubMed  Google Scholar 

  • Monier A, Adle-Biassette H, Delezoide AL, Evrard P, Gressens P, Verney C (2007) Entry and distribution of microglial cells in human embryonic and fetal cerebral cortex. J Neuropathol Exp Neurol 66(5):372–382

    PubMed  Google Scholar 

  • Moore MA, Metcalf D (1970) Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol 18(3):279–296

    CAS  PubMed  Google Scholar 

  • Morris L, Graham CF, Gordon S (1991) Macrophages in haemopoietic and other tissues of the developing mouse detected by the monoclonal antibody F4/80. Development 112(2):517–526

    CAS  PubMed  Google Scholar 

  • Murabe Y, Sano Y (1982) Morphological studies on neuroglia. VI. Postnatal development of microglial cells. Cell Tissue Res 225(3):469–485

    CAS  PubMed  Google Scholar 

  • Naito M, Takahashi K, Nishikawa S (1990) Development, differentiation, and maturation of macrophages in the fetal mouse liver. J Leukoc Biol 48(1):27–37

    CAS  PubMed  Google Scholar 

  • Naito M, Umeda S, Yamamoto T, Moriyama H, Umezu H, Hasegawa G, Usuda H, Shultz LD, Takahashi K (1996) Development, differentiation, and phenotypic heterogeneity of murine tissue macrophages. J Leukoc Biol 59(2):133–138

    CAS  PubMed  Google Scholar 

  • Nandi S, Cioce M, Yeung YG, Nieves E, Tesfa L, Lin H, Hsu AW, Halenbeck R, Cheng HY, Gokhan S, Mehler MF, Stanley ER (2013) Receptor-type protein tyrosine phosphatase zeta is a functional receptor for interleukin-34. J Biol Chem 288(30):21972–21986

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318

    CAS  PubMed  Google Scholar 

  • North T, Gu TL, Stacy T, Wang Q, Howard L, Binder M, Marin-Padilla M, Speck NA (1999) Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development 126(11):2563–2575

    CAS  PubMed  Google Scholar 

  • Orkin SH, Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132(4):631–644

    CAS  PubMed Central  PubMed  Google Scholar 

  • Otero K, Turnbull IR, Poliani PL, Vermi W, Cerutti E, Aoshi T, Tassi I, Takai T, Stanley SL, Miller M, Shaw AS, Colonna M (2009) Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and beta-catenin. Nat Immunol 10(7):734–743

    CAS  PubMed Central  PubMed  Google Scholar 

  • Palis J, Robertson S, Kennedy M, Wall C, Keller G (1999) Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development 126(22): 5073–5084

    CAS  PubMed  Google Scholar 

  • Paloneva J, Kestila M, Wu J, Salminen A, Bohling T, Ruotsalainen V, Hakola P, Bakker AB, Phillips JH, Pekkarinen P, Lanier LL, Timonen T, Peltonen L (2000) Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25(3):357–361

    CAS  PubMed  Google Scholar 

  • Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333(6048):1456–1458

    CAS  PubMed  Google Scholar 

  • Pardo CA, Eberhart CG (2007) The neurobiology of autism. Brain Pathol 17(4):434–447

    CAS  PubMed  Google Scholar 

  • Pascual O, Ben Achour S, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A 109(4):E197–E205

    CAS  PubMed Central  PubMed  Google Scholar 

  • Patterson PH (2009) Immune involvement in schizophrenia and autism: etiology, pathology and animal models. Behav Brain Res 204(2):313–321

    CAS  PubMed  Google Scholar 

  • Peri F, Nusslein-Volhard C (2008) Live imaging of neuronal degradation by microglia reveals a role for v0-ATPase a1 in phagosomal fusion in vivo. Cell 133(5):916–927

    CAS  PubMed  Google Scholar 

  • Perry VH (1998) A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation. J Neuroimmunol 90(2):113–121

    CAS  PubMed  Google Scholar 

  • Perry VH, Hume DA, Gordon S (1985) Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15(2):313–326

    CAS  PubMed  Google Scholar 

  • Perry VH, Nicoll JA, Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol 6(4):193–201

    PubMed  Google Scholar 

  • Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14(10):1227–1235

    CAS  PubMed  Google Scholar 

  • Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122(4):1164–1171

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12(9):623–635

    CAS  PubMed  Google Scholar 

  • Rezaie P (2003) Microglia in the human nervous system during development. Neuroembryology 2:18–31

    Google Scholar 

  • Rezaie P, Male D (1999) Colonisation of the developing human brain and spinal cord by microglia: a review. Microsc Res Tech 45(6):359–382

    CAS  PubMed  Google Scholar 

  • Rezaie P, Male D (2002) Mesoglia & microglia—a historical review of the concept of mononuclear phagocytes within the central nervous system. J Hist Neurosci 11(4):325–374

    PubMed  Google Scholar 

  • Rezaie P, Dean A, Male D, Ulfig N (2005) Microglia in the cerebral wall of the human telencephalon at second trimester. Cereb Cortex 15(7):938–949

    PubMed  Google Scholar 

  • Rio-Hortega, D. (1932). Microglia. In Penfield W, editor. Cytology and cellular pathology of the nervous system 2, pp 483–534

    Google Scholar 

  • Rio-Hortega D (1939) The microglia. Lancet 233(6036):1023–1026

    Google Scholar 

  • Rogers JT, Morganti JM, Bachstetter AD, Hudson CE, Peters MM, Grimmig BA, Weeber EJ, Bickford PC, Gemma C (2011) CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity. J Neurosci 31(45):16241–16250

    CAS  PubMed  Google Scholar 

  • Roumier A, Bechade C, Poncer JC, Smalla KH, Tomasello E, Vivier E, Gundelfinger ED, Triller A, Bessis A (2004) Impaired synaptic function in the microglial KARAP/DAP12-deficient mouse. J Neurosci 24(50):11421–11428

    CAS  PubMed  Google Scholar 

  • Samokhvalov IM, Samokhvalova NI, Nishikawa S (2007) Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature 446(7139):1056–1061

    CAS  PubMed  Google Scholar 

  • Sawada M, Suzumura A, Yamamoto H, Marunouchi T (1990) Activation and proliferation of the isolated microglia by colony stimulating factor-1 and possible involvement of protein kinase C. Brain Res 509(1):119–124

    CAS  PubMed  Google Scholar 

  • Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74(4):691–705

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schlegelmilch T, Henke K, Peri F (2011) Microglia in the developing brain: from immunity to behaviour. Curr Opin Neurobiol 21(1):5–10

    CAS  PubMed  Google Scholar 

  • Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077):86–90

    CAS  PubMed  Google Scholar 

  • Serbina NV, Pamer EG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7(3):311–317

    CAS  PubMed  Google Scholar 

  • Serrats J, Schiltz JC, Garcia-Bueno B, van Rooijen N, Reyes TM, Sawchenko PE (2010) Dual roles for perivascular macrophages in immune-to-brain signaling. Neuron 65(1):94–106

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sierra A, Encinas JM, Deudero JJ, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell 7(4):483–495

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sierra A, Abiega O, Shahraz A, Neumann H (2013) Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci 7:6

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sorokin SP, Hoyt RF Jr, Blunt DG, McNelly NA (1992) Macrophage development: II. Early ontogeny of macrophage populations in brain, liver, and lungs of rat embryos as revealed by a lectin marker. Anat Rec 232(4):527–550

    CAS  PubMed  Google Scholar 

  • Suzuki K, Sugihara G, Ouchi Y, Nakamura K, Futatsubashi M, Takebayashi K, Yoshihara Y, Omata K, Matsumoto K, Tsuchiya KJ, Iwata Y, Tsujii M, Sugiyama T, Mori N (2013) Microglial activation in young adults with autism spectrum disorder. JAMA Psychiatry 70(1):49–58

    PubMed  Google Scholar 

  • Swinnen N, Smolders S, Avila A, Notelaers K, Paesen R, Ameloot M, Brone B, Legendre P, Rigo JM (2013) Complex invasion pattern of the cerebral cortex by microglial cells during development of the mouse embryo. Glia 61(2):150–163

    PubMed  Google Scholar 

  • Takahashi K, Naito M (1993) Development, differentiation, and proliferation of macrophages in the rat yolk sac. Tissue Cell 25(3):351–362

    CAS  PubMed  Google Scholar 

  • Takahashi K, Yamamura F, Naito M (1989) Differentiation, maturation, and proliferation of macrophages in the mouse yolk sac: a light-microscopic, enzyme-cytochemical, immunohistochemical, and ultrastructural study. J Leukoc Biol 45(2):87–96

    CAS  PubMed  Google Scholar 

  • Tambuyzer BR, Ponsaerts P, Nouwen EJ (2009) Microglia: gatekeepers of central nervous system immunology. J Leukoc Biol 85(3):352–370

    CAS  PubMed  Google Scholar 

  • Tavian M, Peault B (2005) Embryonic development of the human hematopoietic system. Int J Dev Biol 49(2–3):243–250

    CAS  PubMed  Google Scholar 

  • Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8(11):e1000527

    PubMed Central  PubMed  Google Scholar 

  • Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J, Ishii M, Yamashita T (2013) Layer V cortical neurons require microglial support for survival during postnatal development. Nat Neurosci 16(5):543–551

    CAS  PubMed  Google Scholar 

  • Vallieres L, Sawchenko PE (2003) Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J Neurosci 23(12):5197–5207

    CAS  PubMed  Google Scholar 

  • van Rooijen N, Bakker J, Sanders A (1997) Transient suppression of macrophage functions by liposome-encapsulated drugs. Trends Biotechnol 15(5):178–185

    PubMed  Google Scholar 

  • Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA (2005) Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol 57(1):67–81

    CAS  PubMed  Google Scholar 

  • Venneti S, Lopresti BJ, Wiley CA (2006) The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: from pathology to imaging. Prog Neurobiol 80(6):308–322

    CAS  PubMed Central  PubMed  Google Scholar 

  • Verney C, Monier A, Fallet-Bianco C, Gressens P (2010) Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants. J Anat 217(4):436–448

    PubMed Central  PubMed  Google Scholar 

  • Volpe JJ (2001) Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res 50(5):553–562

    CAS  PubMed  Google Scholar 

  • Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29(13):3974–3980

    CAS  PubMed  Google Scholar 

  • Wakselman S, Bechade C, Roumier A, Bernard D, Triller A, Bessis A (2008) Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J Neurosci 28(32):8138–8143

    CAS  PubMed  Google Scholar 

  • Wang CC, Wu CH, Shieh JY, Wen CY, Ling EA (1996) Immunohistochemical study of amoeboid microglial cells in fetal rat brain. J Anat 189(Pt 3):567–574

    PubMed Central  PubMed  Google Scholar 

  • Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, Barrow AD, Diamond MS, Colonna M (2012) IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13(8):753–760

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wei S, Nandi S, Chitu V, Yeung YG, Yu W, Huang M, Williams LT, Lin H, Stanley ER (2010) Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol 88(3):495–505

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER (1990) Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A 87(12):4828–4832

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wolf Y, Yona S, Kim KW, Jung S (2013) Microglia, seen from the CX3CR1 angle. Front Cell Neurosci 7:26

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis and disease. Nature 496(7446):445–455

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang I, Han SJ, Kaur G, Crane C, Parsa AT (2010) The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17(1):6–10

    PubMed Central  PubMed  Google Scholar 

  • Yokomizo T, Dzierzak E (2010) Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos. Development 137(21):3651–3661

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen B, Zelzer E, Jung S (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38(1):79–91

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345(6274):442–444

    CAS  PubMed  Google Scholar 

  • Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR (2007) Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine. Brain Behav Immun 21(5):642–651

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Singapore Immunology Network core grant (FG and GH). We thank Dr. L. Robinson of Insight Editing London for critical review and editing of the manuscript. SG is supported by the INSERM and the recipient of EURYI and EMBO YIP awards.

Author information

Authors and Affiliations

  1. Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos Building, Level 3, Biopolis, Singapore, 138648, Singapore

    Guillaume Hoeffel & Florent Ginhoux

  2. Ecole Normale Supérieure, Institut de Biologie de l’ENS, IBENS, INSERM, U1024, Avenir Team, CNRS, UMR 8197, 46 rue d’Ulm, 75230, Paris Cedex 05, France

    Paola Squarzoni & Sonia Garel

Authors
  1. Guillaume Hoeffel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Squarzoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sonia Garel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Florent Ginhoux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sonia Garel or Florent Ginhoux .

Editor information

Editors and Affiliations

  1. Singapore Immunology Network (SIgN) Biomedical Sciences Institutes, A*STAR, Singapore, Singapore

    Subhra K. Biswas

  2. IRCCS Humanitas Clinical and Research Institute, Humanitas University, Rozzano, Italy

    Alberto Mantovani

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Hoeffel, G., Squarzoni, P., Garel, S., Ginhoux, F. (2014). Microglial Ontogeny and Functions in Shaping Brain Circuits. In: Biswas, S., Mantovani, A. (eds) Macrophages: Biology and Role in the Pathology of Diseases. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1311-4_9

Download citation

Publish with us

Policies and ethics

Search

Navigation