Skip to main content
Log in

Distribution and Morphological Features of Microglia in the Developing Cerebral Cortex of Gyrencephalic Mammals

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Microglia have been attracting much attention because of their fundamental importance in both the mature brain and the developing brain. Though important roles of microglia in the developing cerebral cortex of mice have been uncovered, their distribution and roles in the developing cerebral cortex in gyrencephalic higher mammals have remained elusive. Here we examined the distribution and morphology of microglia in the developing cerebral cortex of gyrencephalic carnivore ferrets. We found that a number of microglia were accumulated in the germinal zones (GZs), especially in the outer subventricular zone (OSVZ), which is a GZ found in higher mammals. Furthermore, we uncovered that microglia extended their processes tangentially along inner fiber layer (IFL)-like fibers in the developing ferret cortex. The OSVZ and the IFL are the prominent features of the cerebral cortex of higher mammals. Our findings indicate that microglia may play important roles in the OSVZ and the IFL in the developing cerebral cortex of higher mammals.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CP:

Cortical plate

GZ:

Germinal zone

IFL:

Inner fiber layer

ISVZ:

Inner subventricular zone

IZ:

Intermediate zone

OSVZ:

Outer subventricular zone

VZ:

Ventricular zone

References

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

    Article  CAS  PubMed  Google Scholar 

  2. Pont-Lezica L, Bechade C, Belarif-Cantaut Y, Pascual O, Bessis A (2011) Physiological roles of microglia during development. J Neurochem 119:901–908

    Article  CAS  PubMed  Google Scholar 

  3. Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci 31:16064–16069

    Article  CAS  PubMed  Google Scholar 

  4. 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 8:752–758

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Andjelkovic AV, Nikolic B, Pachter JS, Zecevic N (1998) Macrophages/microglial cells in human central nervous system during development: an immunohistochemical study. Brain Res 814:13–25

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. 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 61:150–163

    Article  PubMed  Google Scholar 

  9. 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 217:436–448

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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 330:841–845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. 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 117:145–152

    Article  CAS  PubMed  Google Scholar 

  13. 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 336:86–90

    Article  CAS  PubMed  Google Scholar 

  14. 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 16:273–280

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Cuadros MA, Martin C, Coltey P, Almendros A, Navascues J (1993) First appearance, distribution, and origin of macrophages in the early development of the avian central nervous system. J Comp Neurol 330:113–129

    Article  CAS  PubMed  Google Scholar 

  17. 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 16:543–551

    Article  CAS  PubMed  Google Scholar 

  18. Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P, Low D, Bessis A, Ginhoux F, Garel S (2014) Microglia modulate wiring of the embryonic forebrain. Cell Rep 8:1271–1279

    Article  CAS  PubMed  Google Scholar 

  19. Borrell V, Gotz M (2014) Role of radial glial cells in cerebral cortex folding. Curr Opin Neurobiol 27:39–46

    Article  CAS  PubMed  Google Scholar 

  20. Namba T, Huttner WB (2017) Neural progenitor cells and their role in the development and evolutionary expansion of the neocortex. Wiley Interdiscip Rev Dev Biol 6:e256

    Article  Google Scholar 

  21. Kriegstein A, Noctor S, Martinez-Cerdeno V (2006) Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nat Rev Neurosci 7:883–890

    Article  CAS  PubMed  Google Scholar 

  22. Lui JH, Hansen DV, Kriegstein AR (2011) Development and evolution of the human neocortex. Cell 146:18–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Molnar Z, Clowry G (2012) Cerebral cortical development in rodents and primates. Prog Brain Res 195:45–70

    Article  PubMed  Google Scholar 

  24. Poluch S, Juliano SL (2015) Fine-tuning of neurogenesis is essential for the evolutionary expansion of the cerebral cortex. Cereb Cortex 25:346–364

    Article  PubMed  Google Scholar 

  25. Rakic P (2009) Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10:724–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sun T, Hevner RF (2014) Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat Rev Neurosci 15:217–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kawasaki H (2017) Molecular investigations of development and diseases of the brain of higher mammals using the ferret. Proc Jpn Acad B 93:259–269

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zilles K, Palomero-Gallagher N, Amunts K (2013) Development of cortical folding during evolution and ontogeny. Trends Neurosci 36:275–284

    Article  CAS  PubMed  Google Scholar 

  29. Zecevic N, Chen Y, Filipovic R (2005) Contributions of cortical subventricular zone to the development of the human cerebral cortex. J Comp Neurol 491:109–122

    Article  PubMed  PubMed Central  Google Scholar 

  30. Smart IH, Dehay C, Giroud P, Berland M, Kennedy H (2002) Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb Cortex 12:37–53

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kawasaki H, Toda T, Tanno K (2013) In vivo genetic manipulation of cortical progenitors in gyrencephalic carnivores using in utero electroporation. Biol Open 2:95–100

    Article  PubMed  Google Scholar 

  32. Fietz SA, Kelava I, Vogt J, Wilsch-Brauninger M, Stenzel D, Fish JL, Corbeil D, Riehn A, Distler W, Nitsch R, Huttner WB (2010) OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat Neurosci 13:690–699

    Article  CAS  PubMed  Google Scholar 

  33. Reillo I, de Juan Romero C, Garcia-Cabezas MA, Borrell V (2011) A role for intermediate radial glia in the tangential expansion of the mammalian cerebral cortex. Cereb Cortex 21:1674–1694

    Article  PubMed  Google Scholar 

  34. Berman NE, Johnson JK, Klein RM (1997) Early generation of glia in the intermediate zone of the developing cerebral cortex. Brain Res Dev Brain Res 101:149–164

    Article  CAS  PubMed  Google Scholar 

  35. Kawasaki H, Crowley JC, Livesey FJ, Katz LC (2004) Molecular organization of the ferret visual thalamus. J Neurosci 24:9962–9970

    Article  CAS  PubMed  Google Scholar 

  36. Iwai L, Ohashi Y, van der List D, Usrey WM, Miyashita Y, Kawasaki H (2013) FoxP2 is a parvocellular-specific transcription factor in the visual thalamus of monkeys and ferrets. Cereb Cortex 23:2204–2212

    Article  PubMed  Google Scholar 

  37. Shinmyo Y, Terashita Y, Dinh Duong TA, Horiike T, Kawasumi M, Hosomichi K, Tajima A, Kawasaki H (2017) Folding of the cerebral cortex requires Cdk5 in upper-layer neurons in gyrencephalic mammals. Cell Rep 20:2131–2143

    Article  CAS  PubMed  Google Scholar 

  38. Kawasaki H, Iwai L, Tanno K (2012) Rapid and efficient genetic manipulation of gyrencephalic carnivores using in utero electroporation. Mol Brain 5:24

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sehara K, Toda T, Iwai L, Wakimoto M, Tanno K, Matsubayashi Y, Kawasaki H (2010) Whisker-related axonal patterns and plasticity of layer 2/3 neurons in the mouse barrel cortex. J Neurosci 30:3082–3092

    Article  CAS  PubMed  Google Scholar 

  40. Hoshiba Y, Toda T, Ebisu H, Wakimoto M, Yanagi S, Kawasaki H (2016) Sox11 balances dendritic morphogenesis with neuronal migration in the developing cerebral cortex. J Neurosci 36:5775–5784

    Article  CAS  PubMed  Google Scholar 

  41. Wakimoto M, Sehara K, Ebisu H, Hoshiba Y, Tsunoda S, Ichikawa Y, Kawasaki H (2015) Classic cadherins mediate selective intracortical circuit formation in the mouse neocortex. Cereb Cortex 25:3535–3546

    Article  PubMed  Google Scholar 

  42. Hayakawa I, Kawasaki H (2010) Rearrangement of retinogeniculate projection patterns after eye-specific segregation in mice. PLoS ONE 5:e11001

    Article  PubMed  PubMed Central  Google Scholar 

  43. Iwai L, Kawasaki H (2009) Molecular development of the lateral geniculate nucleus in the absence of retinal waves during the time of retinal axon eye-specific segregation. Neuroscience 159:1326–1337

    Article  CAS  PubMed  Google Scholar 

  44. Toda T, Hayakawa I, Matsubayashi Y, Tanaka K, Ikenaka K, Lu QR, Kawasaki H (2008) Termination of lesion-induced plasticity in the mouse barrel cortex in the absence of oligodendrocytes. Mol Cell Neurosci 39:40–49

    Article  CAS  PubMed  Google Scholar 

  45. Bin JM, Harris SN, Kennedy TE (2016) The oligodendrocyte-specific antibody ‘CC1’ binds Quaking 7. J Neurochem 139:181–186

    Article  CAS  PubMed  Google Scholar 

  46. 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 74:691–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schwarz JM, Sholar PW, Bilbo SD (2012) Sex differences in microglial colonization of the developing rat brain. J Neurochem 120:948–963

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lenz KM, Nugent BM, Haliyur R, McCarthy MM (2013) Microglia are essential to masculinization of brain and behavior. J Neurosci 33:2761–2772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kloss CU, Bohatschek M, Kreutzberg GW, Raivich G (2001) Effect of lipopolysaccharide on the morphology and integrin immunoreactivity of ramified microglia in the mouse brain and in cell culture. Exp Neurol 168:32–46

    Article  CAS  PubMed  Google Scholar 

  50. Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33:256–266

    Article  CAS  PubMed  Google Scholar 

  51. Yamada M, Ohsawa K, Imai Y, Kohsaka S, Kamitori S (2006) X-ray structures of the microglia/macrophage-specific protein Iba1 from human and mouse demonstrate novel molecular conformation change induced by calcium binding. J Mol Biol 364:449–457

    Article  CAS  PubMed  Google Scholar 

  52. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 57:1–9

    Article  CAS  PubMed  Google Scholar 

  53. Jackson CA, Peduzzi JD, Hickey TL (1989) Visual cortex development in the ferret. I. Genesis and migration of visual cortical neurons. J Neurosci 9:1242–1253

    Article  CAS  PubMed  Google Scholar 

  54. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    Article  CAS  PubMed  Google Scholar 

  55. Davis EJ, Foster TD, Thomas WE (1994) Cellular forms and functions of brain microglia. Brain Res Bull 34:73–78

    Article  CAS  PubMed  Google Scholar 

  56. Petersen MA, Dailey ME (2004) Diverse microglial motility behaviors during clearance of dead cells in hippocampal slices. Glia 46:195–206

    Article  PubMed  Google Scholar 

  57. Reemst K, Noctor SC, Lucassen PJ, Hol EM (2016) The indispensable roles of microglia and astrocytes during brain development. Front Hum Neurosci 10:566

    Article  PubMed  PubMed Central  Google Scholar 

  58. Xavier AL, Menezes JR, Goldman SA, Nedergaard M (2014) Fine-tuning the central nervous system: microglial modelling of cells and synapses. Philos Trans R Soc Lond B 369:20130593

    Article  Google Scholar 

  59. Pont-Lezica L, Beumer W, Colasse S, Drexhage H, Versnel M, Bessis A (2014) Microglia shape corpus callosum axon tract fasciculation: functional impact of prenatal inflammation. Eur J Neurosci 39:1551–1557

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to Drs. Eisuke Nishida (Kyoto University), Shigetada Nakanishi (Suntory Foundation for Life Science) and the late Yoshiki Sasai and for their continuous encouragement. We thank Zachary Blalock and Kawasaki lab members for their helpful support. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan Agency for Medical Research and Development, the Uehara Memorial Foundation and Takeda Science Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiroshi Kawasaki.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2295 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mizuguchi, K., Horiike, T., Matsumoto, N. et al. Distribution and Morphological Features of Microglia in the Developing Cerebral Cortex of Gyrencephalic Mammals. Neurochem Res 43, 1075–1085 (2018). https://doi.org/10.1007/s11064-018-2520-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-018-2520-0

Keywords

Navigation