The origin and differentiation of microglial cells during development
Introduction
Microglial cells were reported to exist within the central nervous system (CNS) nearly a century ago [see Barron (1995)]. Although del Rio-Hortega (1932)provided a complete framework for defining this cell type, many features of microglia are still controversial. An example is the two opposing hypotheses on the origin of microglial precursors that continue to be defended more than half a century after del Rio-Hortega's paper. One hypothesis states that microglial precursors are cells of neuroectodermal origin like neurons and the remaining glial cells; the other proposes that they proceed from mesodermal cells and therefore originate outside the developing nervous tissue. If the second theory is true, how and when microglia precursors enter the nervous parenchyma must be determined. Regardless of their origin, these cells must migrate through and differentiate in the entire CNS.
This review deals with the origin and development of microglia within the developing normal brain. It is convenient to distinguish between:
- 1.
the production of microglia during development; and
- 2.
the origin and differentiation of cells responsible for microglial turnover in adult life and microglial production under pathological conditions (cerebral ischemia, infection, mechanical or chemical injury,…), because different mechanism are probably involved in these situations.
This article refers only to the first topic; readers interested in the biology of the adult microglia and their function in the normal and pathological brain should consult recent reviews (Perry and Gordon, 1991; Thomas, 1992; Banati et al., 1993; Banati and Graeber, 1994; Barron, 1995; Gehrmann et al., 1995; Streit, 1995; Kreutzberg, 1996; Moore and Thanos, 1996).
Section snippets
Origin of microglia
As indicated already, two principal views about the origin of microglia currently exist:
- 1.
microglial cells are of mesodermal origin; and
- 2.
microglial cells originate from neuroepithelial cells.
View (1) is sustained by a large proportion of authors, who believe that microglia derive either from monocytes that leave the blood stream and colonize the nervous parenchyma, or from primitive (or stem) hemopoietic cells that differentiate as microglial cells within the CNS.
Invasion of the developing CNS by microglial precursors
If microglial precursors originate outside the nervous parenchyma, they need to enter it at some point. This probably occurs for the most part before the nervous system is mature. In the quail many microglial precursors enter the nervous parenchyma during the last week of incubation (Cuadros et al., 1994, Cuadros et al., 1997; Navascués et al., 1995), and they appear for the first time within the rodent nervous system during the end of embryonic life and first days of postnatal life (Perry et
Spreading of microglial precursors within the CNS: proliferation and migration
Microglial cells appear in all regions of the mature CNS, although their density varies between areas of the nervous parenchyma (Lawson et al., 1990). Two mechanisms may contribute to the spreading of microglial cells throughout the nervous parenchyma: proliferation and migration.
Differentiation of microglial cells
Microglial cells apparently pass through different stages of development (Fig. 5). In the first stage, ameboid microglia, have morphological, histochemical and immunological features similar to those of macrophages outside the CNS, and are therefore also known as brain macrophages. Ameboid microglia are round or have short, broad processes; presumably, cells of dendritic or elongated morphology also belong to this type of microglia, as seen in the developing retina, tectum and cerebellum of the
Role of microglial cells during development
Microglial cells participate in many of the complex morphogenetic and histogenetic processes which take place during the development of CNS in order to establish the complex network of connections present in the adult. They remove dead cell fragments (Ferrer et al., 1990; Ashwell, 1990, Ashwell, 1991) and eliminate transitory or aberrant axons (Innocenti et al., 1983; Ashwell, 1990). In addition to acting as scavengers of cell and axon debris, microglial cells may also play more active roles
Conclusions
Fig. 7 provides a summary of the proposed process of microglial cell appearance during development. Although controversy still exists, some events are likely to occur:
- 1.
Microglial cells derive from blood cells, or more likely, from cells of the blood cell lineage.
- 2.
During development microglial precursors enter the CNS via different routes: from the meninges, from the ventricular lumen or from the blood stream.
- 3.
Precursors migrate within the nervous parenchyma to their final location.
- 4.
Microglial cells
Acknowledgements
Thanks are due to A. Almendros, R. Calvente, J. L. Marı́n-Teva, A. Moujahid, A. Quesada and J. Rodrı́guez-Ruiz, who participated in original work at our laboratory that is reported here. The authors are grateful to Dr B. Castellano for his critical reading of the manuscript. They would also like to thank Karen Shasok for improving the English style of the manuscript. Work at our laboratory was supported by Grant No. PB94-0789 from the Dirección General de Investigación Cientı́fica y Técnica
References (177)
- et al.
Brain microglia constitutively express β-2 integrins
J. Neuroimmunol.
(1990) - et al.
Early response of brain resident microglia to kainic acid-induced hippocampal lesions
Brain Res.
(1994) Microglia and cell death in the developing mouse cerebellum
Dev. Brain Res.
(1990)The distribution of microglia and cell death in the fetal rat forebrain
Dev. Brain Res.
(1991)The microglial cell. A historical review
J. Neurol. Sci.
(1995)- et al.
Microglia and the developing olfactory bulb
Neuroscience
(1993) - et al.
Fibronectin and laminin regulate the in vitro differentiation of microglial cells
Neuroscience
(1991) - et al.
Immunohistochemical detection of thrombospondin in microglia in the developing rat brain
Neuroscience
(1995) - et al.
Microglia in the mature and developing quail brain as revealed by a monoclonal antibody recognizing hemopoietic cells
Neurosci. Lett.
(1992) - et al.
Expression of LFA-1a and ICAM-1 in the developing rat brain: a potential mechanism for the recruitment of microglial cell precursors
Dev. Brain Res.
(1997)