RADIAL GLIAL CELLS. key organisers in CNS development

RADIAL GLIAL CELLS: key organisers in CNS development
Denis S. Barry*, Janelle M.P. Pakan† and Kieran W. McDermott†
*Department of Anatomy, Trinity College Dublin, Dublin, Ireland.
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
*Corresponding author
Denis Barry
Department of Anatomy
Trinity College Dublin
Email: [email protected]
Phone: + 353 1 8961793
Radial glia are elongated bipolar cells present in the CNS during development. Our
understanding of the unique roles these cells play has significantly expanded in the last
decade. Historically, radial glial cells were primarily thought to provide an architectural
framework for neuronal migration. Recent research reveals that radial glia play a more
dynamic and integrated role in the development of the brain and spinal cord. They represent a
major progenitor pool during early development and can give rise to a small population of
multipotent cells in neurogenic niches of the adult CNS. Radial glial cells are a
heterogeneous population, with divergent and often poorly understood roles across different
brain and spinal cord regions during development; this heterogeneity extends to specialized
adult subtypes, such as tanycytes, Müller glial cells and Bergman glial cells which possess
morphological similarities to radial glial but play distinct functional roles in the CNS.
Keywords: Radial glia, neurodevelopment, neuronal migration, glioma
Cell Facts
Radial glial cells differentiate from neuroepithelial cells in the developing CNS.
Radial glial cells possess an elongated radial process spanning the CNS from the
ventricular zone to the pial surface.
Radial glial cells have multifunctional roles; they provide structural support during axon
growth, they act as a scaffold for neuronal migration.
Radial glial cells are important progenitor cells contributing to gliogenesis in all regions
and additionally to neurogenesis in the mammalian cerebral cortex.
Radial glial cells are a transient cell type present mainly during development although a
few exceptional radial glial-like cell populations exist into adulthood.
Alterations in the radial glial cell network during development may lead to disorganized
CNS tissues resulting in different neurodevelopmental disorders.
Radial glial cells have been the subject of much interest during the on-going efforts to
understand CNS formation. This cell type, with its long radial process, was originally
discovered spanning the foetal spinal cord by Camillo Golgi in 1885 (Rakic, 2003). Ramon
Cajal originally suggested a glial identity for these cells by demonstrating their
morphological similarities with astrocytes, but their glial phenotype was ultimately confirmed
60 years later when immunohistochemistry and electron microscopy showed that radial glial
cells contain glycogen granules and GFAP, which are intracellular characteristics found only
in glia (Choi, 1981; Levitt & Rakic, 1980). Today, radial glial cells are recognised as
morphologically, biochemically and functionally distinct from other neural cell types. They
display an apical - basal polarity possessing a periventricular cell body and an elongated
process extending from a ventricular attachment to an end-foot anchored to the opposing pial
surface (Fig. 1A, B). Some radial glia are thought to persist into adult life, albeit in very
limited numbers, and some in specific neurogenic niches. Radial glia subtypes have also been
identified, including tanycytes around the ventricles, Müller glia in the retina and Bergmann
glia in the cerebellum (Fig. 1C-E). Notably, both Müller and Bergmann glia preserve their
radial morphology postnatally (Guo et al, 2013; Surzenko et al, 2013).
The classical role of radial glia is in neuronal migration (Rakic, 1972), acting as
guidance cables aiding the migration of new-born neurons; however, modern cell fate
determination and imaging methodologies have revealed that radial glia are also
multifunctional neural stem cells that structurally orchestrate CNS organization and generate
different cells types, conforming to the needs of the different neural compartments they
Cell origin and plasticity
Neuroepithelial cells arise from the ectoderm early in development, divide symmetrically and
generate the neural plate. This invaginates to form the neural tube, the width of which is
occupied by a polarised pseudostratified neuroepithelium. Neuroepithelial cells possess a
basal side attached to the pial surface and an apical side that contacts the lumen of the neural
tube. As development proceeds, they multiply and form the CNS germinal zones, namely the
ventricle zone and subventricular zones. Here, neuroepithelial cells, most of which by now
have a radial morphology and are termed radial neuroepithelial cells, serve as neural stem
cells, expanding the CNS by self-renewing and populating it by generating neurons and glia.
After completing the early phases of neurogenesis, they begin their transformation into radial
glial cells. This is initiated by the down regulation of epithelial features, such as tight
junctions (Aaku-Saraste et al, 1996) and completed by the up regulation of glial specific
identifiers such as the membrane proteins GLAST and BLBP (Morest & Silver, 2003) and
the appearance of cytoplasmic glycogen granules (Gadisseux & Evrard, 1985). Radial glial
cells and radial neuroepithelial cells express the intermediate filament nestin (Hartfuss et al,
2001) and both undergo interkinetic neuronal migration (LaMonica et al, 2013; Tsai et al,
2010). While this developmental sequence of events appears to be consistent for many CNS
radial glia, in the cerebral cortex they retain the capacity to generate large numbers of
neurons. In regions other than the cerebral cortex, the contribution of differentiated radial glia
to on-going neurogenesis is unclear. In the spinal cord and cerebellum, their appearance
temporally precedes the first appearance of astrocytes and oligodendrocytes suggesting that
here most radial glia bypass neurogenesis, and adopt a glial fate after fulfilling their guidance
(Rakic, 2003) and boundary forming functions (Barry et al, 2013).
Cell functions
Radial glia and their subtypes show extraordinary adaptability facilitating the
formation of the cerebellum, hypothalamus, cerebral cortex, and spinal cord. While their roles
in different CNS regions can overlap, their functions seem to depend on the developmental
status of the brain region they occupy. Their longest established and best characterised
function is in neuronal migration, intricately guiding new-born neurons from germinal zones
to their target destinations in the correct lamina of the cerebral cortex (Fig. 2A, B) (Rakic,
1972; Xu et al, 2013). It is not clear whether or not radial glia support neuronal migration in
the developing spinal cord, but it seems unlikely as neurogenesis and neuronal migration
largely precede the differentiation of radial glia from the neuroepithelium (Barry &
McDermott, 2005).
Radial glia are now considered key progenitor cells, comprising the majority of
mitotically active cells in brain ventricular zones (Lui et al, 2011; Malatesta & Gotz, 2013;
Pilz et al, 2013). Subsequently, many clearly differentiate into astrocytes later in development
(Noctor et al, 2004). Moreover, recent in vivo genetic fate mapping experiments have
revealed that some radial glia in the cerebral cortex are lineage restricted to generating upper
layer neurons, implicating them in human brain evolution (Franco et al, 2012). These stem
cell roles for radial glia have transformed the heretofore prevailing view of separate
neuroepithelial lineages for neurons and glia. However, as much of this evidence has been
obtained using different experimental techniques, in different regions and across different
species, it seems premature to assume that all radial glia generate neurons in all regions of the
Apart from their stem cell and neuronal migration roles, radial glia cells also facilitate
the formation and compartmentalisation of the white matter (Steindler, 1993). For example,
axons forming the corpus callosum grow within a transient glial ‘sling’, which is most likely
composed of radial glia, that disappears around the perinatal period (Silver et al, 1982). In the
spinal cord, finely organised radial glial processes also create boundaries which separate
nascent axon tracts in the emerging dorsal and lateral white matter (Fig. 2C, D) (Barry et al,
2013). These recent observations demonstrate new temporally separated roles for spinal cord
radial glia; firstly, organising axonogenesis and then, when axon tracts have matured,
generating glial cells.
Recent data have also implicated radial glia in the regulation of cerebral cortical
vascularisation via modulation of canonical Wnt signalling (Ma et al, 2013). Indeed,
inhibition of radial glial cell division in developing cerebral cortex of Orc3 knockout mice
leads to neonatal cerebral haemorrhage resulting in major reductions in vessel density and
branch point frequency (Ma et al, 2013). This implicates radial glia in the pathogenesis of
new-born cerebrovascular diseases, such as perinatal haemorrhagic stroke.
Associated Pathologies
As described, radial glia give rise to nearly all cortical neurons and glia and serve as
neuronal migration conduits. Therefore, dysfunction of radial glial cell cycle has catastrophic
consequences for brain lamination. Lissencephaly and micro-lissencephaly (smooth brain) are
neurodevelopmental diseases caused by defects in neurogenesis and neural migration and
result in reduced brain volume and a lack of cortical sulci and gyri at birth. Affected patients
may experience mental retardation, motor and speech dysfunction, balance problems, and
epilepsy. More extreme cases result in death within a few months of life (Wu & Wang,
2012). Microlissencephaly and lissencephaly are associated with the radial glial intracellular
scaffold protein’s Lis1 and its binding partner Nde1 (Alkuraya et al, 2011; Reiner et al,
1993), which aid in microtubule organisation and play an essential role in radial glial
differentiation (Pawlisz & Feng, 2011). Animal models lacking Lis1 and Nde1 show severe
neurogenesis and neuronal migration abnormalities (Pawlisz & Feng, 2011). Further insight
into the precise mechanisms underlying how radial glia mediate neuronal migration are
essential when considering the pathologies resulting from lissencephaly and other
developmental disorders that cause abnormal migration, such as foetal alcohol syndrome.
Gliomas are the most common adult brain tumours and often the most lethal. Some
are thought to originate during development (Vick et al, 1977) and oncogenic cells have been
linked to progenitor cell populations resident not only during development, but also in the
adult (Sanai et al, 2005; Wu & Wang, 2012). It is not unsurprising, therefore, that radial glia
are recognised as potential targets of oncogenic inducers and have high potential for
malignant transformation (De Rosa et al, 2012; Wu & Wang, 2012). A full understanding of
the lifecycle of a neural stem cell will be central to our understanding of embryonic brain
tumorigenesis and related developmental diseases.
The authors wish to acknowledge funding from the following sources: The Health
Research Board of Ireland, Programme for Research in Third Level Institutions, The Irish
Research Council.
Figure Legends
Figure 1. Radial glial cells and radial glial-like subtypes in the embryonic and adult CNS. A)
Radial glial cell bodies are present in the ventricular zone (VZ) of the developing spinal cord.
Their processes extend from the central canal (CC) through developing white matter (WM) to
the pial surface. B) Radial glia in the developing cerebral cortex also have cell bodies in the
VZ and their processes extend though the sub-ventricular zone (SVZ) and the developing
cortical plate (CP) to the pial surface. C) Tanycytes in the adult hypothalamus have cell
bodies adjacent to the third ventricle (3V) and processes that extend to the pial surface. D) In
the adult cerebellar cortex Bergmann glia have cell bodies in the Purkinje cell layer (PCL)
and extend highly branched processes through the molecular layer (ML) to the pial surface.
E) Müller glia in the adult retina are large elongated cells extending from the photoreceptors
(PR) to the ganglion cell layer (GCL). Median eminence (ME), arcuate nucleus (AN),
ventromedial hypothalamus (VMH), granule cell layer (GL), inner and outer nuclear layer
(INL and ONL), inner and outer plexiform layer (IPL and OPL).
Figure 2. Radial glial cell structure and function in the developing CNS. A) Progenitor cell
potential of neuroepithelial cells and radial glia during development. Neuroepithelial cells
proliferate and generate neuroblasts and immature neurons. They then differentiate into radial
glia which proliferate and elongate. Radial glia in the cortex contribute to neurogenesis
directly or via immediate neuronal precursor cells (nIPC). Cortical and spinal cord radial glia
contribute to gliogenesis by producing astrocytes (light blue) and possibly oligodendrocytes.
Some radial glia may also differentiate into ependymal cells which line the ventricles of the
adult CNS. B) Radial glia proliferate at the apical surface of the VZ and serve as scaffolds for
newly formed neurons to migrate through the SVZ and into the developing CP. This process
may also facilitate the migration of radial glial cell derived astrocytes. C) BLBP-expressing
radial glial processes form structural boundaries in the spinal cord, delineating the putative
dorsal columns cord (inset). D) A 3-dimensional cross-section view of the embryonic spinal
cord (see red inset schematic) showing BLBP-expressing radial glia forming distinct
corridors (arrows) in the white matter, through which axons may grow. Scale bars = 50 µm.
Aaku-Saraste E, Hellwig A, Huttner WB (1996) Loss of occludin and functional tight
junctions, but not ZO-1, during neural tube closure--remodeling of the neuroepithelium prior
to neurogenesis. Developmental biology 180: 664-679
Alkuraya FS, Cai X, Emery C, Mochida GH, Al-Dosari MS, Felie JM, Hill RS, Barry BJ,
Partlow JN, Gascon GG, Kentab A, Jan M, Shaheen R, Feng Y, Walsh CA (2011) Human
mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]. American
journal of human genetics 88: 536-547
Barry D, McDermott K (2005) Differentiation of radial glia from radial precursor cells and
transformation into astrocytes in the developing rat spinal cord. Glia 50: 187-197
Barry DS, Pakan JM, O'Keeffe GW, McDermott KW (2013) The spatial and temporal
arrangement of the radial glial scaffold suggests a role in axon tract formation in the
developing spinal cord. Journal of anatomy 222: 203-213
Choi BH (1981) Radial glia of developing human fetal spinal cord: Golgi,
immunohistochemical and electron microscopic study. Brain research 227: 249-267
De Rosa A, Pellegatta S, Rossi M, Tunici P, Magnoni L, Speranza MC, Malusa F, Miragliotta
V, Mori E, Finocchiaro G, Bakker A (2012) A radial glia gene marker, fatty acid binding
protein 7 (FABP7), is involved in proliferation and invasion of glioblastoma cells. PloS one
7: e52113
Franco SJ, Gil-Sanz C, Martinez-Garay I, Espinosa A, Harkins-Perry SR, Ramos C, Muller U
(2012) Fate-restricted neural progenitors in the mammalian cerebral cortex. Science 337:
Gadisseux JF, Evrard P (1985) Glial-neuronal relationship in the developing central nervous
system. A histochemical-electron microscope study of radial glial cell particulate glycogen in
normal and reeler mice and the human fetus. Developmental neuroscience 7: 12-32
Guo Z, Wang X, Xiao J, Wang Y, Lu H, Teng J, Wang W (2013) Early postnatal GFAPexpressing cells produce multilineage progeny in cerebrum and astrocytes in cerebellum of
adult mice. Brain research 1532: 14-20
Hartfuss E, Galli R, Heins N, Gotz M (2001) Characterization of CNS precursor subtypes and
radial glia. Developmental biology 229: 15-30
LaMonica BE, Lui JH, Hansen DV, Kriegstein AR (2013) Mitotic spindle orientation
predicts outer radial glial cell generation in human neocortex. Nature communications 4:
Levitt P, Rakic P (1980) Immunoperoxidase localization of glial fibrillary acidic protein in
radial glial cells and astrocytes of the developing rhesus monkey brain. The Journal of
comparative neurology 193: 815-840
Lui JH, Hansen DV, Kriegstein AR (2011) Development and evolution of the human
neocortex. Cell 146: 18-36
Ma S, Kwon HJ, Johng H, Zang K, Huang Z (2013) Radial glial neural progenitors regulate
nascent brain vascular network stabilization via inhibition of Wnt signaling. PLoS biology
11: e1001469
Malatesta P, Gotz M (2013) Radial glia - from boring cables to stem cell stars. Development
140: 483-486
Morest DK, Silver J (2003) Precursors of neurons, neuroglia, and ependymal cells in the
CNS: what are they? Where are they from? How do they get where they are going? Glia 43:
Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR (2004) Cortical neurons arise in
symmetric and asymmetric division zones and migrate through specific phases. Nature
neuroscience 7: 136-144
Pawlisz AS, Feng Y (2011) Three-dimensional regulation of radial glial functions by Lis1Nde1 and dystrophin glycoprotein complexes. PLoS biology 9: e1001172
Pilz GA, Shitamukai A, Reillo I, Pacary E, Schwausch J, Stahl R, Ninkovic J, Snippert HJ,
Clevers H, Godinho L, Guillemot F, Borrell V, Matsuzaki F, Gotz M (2013) Amplification of
progenitors in the mammalian telencephalon includes a new radial glial cell type. Nature
communications 4: 2125
Rakic P (1972) Mode of cell migration to the superficial layers of fetal monkey neocortex.
The Journal of comparative neurology 145: 61-83
Rakic P (2003) Developmental and evolutionary adaptations of cortical radial glia. Cerebral
cortex 13: 541-549
Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns WB, Caskey CT,
Ledbetter DH (1993) Isolation of a Miller-Dieker lissencephaly gene containing G protein
beta-subunit-like repeats. Nature 364: 717-721
Sanai N, Alvarez-Buylla A, Berger MS (2005) Neural stem cells and the origin of gliomas.
The New England journal of medicine 353: 811-822
Silver J, Lorenz SE, Wahlsten D, Coughlin J (1982) Axonal guidance during development of
the great cerebral commissures: descriptive and experimental studies, in vivo, on the role of
preformed glial pathways. The Journal of comparative neurology 210: 10-29
Steindler DA (1993) Glial boundaries in the developing nervous system. Annual review of
neuroscience 16: 445-470
Surzenko N, Crowl T, Bachleda A, Langer L, Pevny L (2013) SOX2 maintains the quiescent
progenitor cell state of postnatal retinal Muller glia. Development 140: 1445-1456
Tsai JW, Lian WN, Kemal S, Kriegstein AR, Vallee RB (2010) Kinesin 3 and cytoplasmic
dynein mediate interkinetic nuclear migration in neural stem cells. Nature neuroscience 13:
Vick NA, Lin MJ, Bigner DD (1977) The role of the subependymal plate in glial
tumorigenesis. Acta neuropathologica 40: 63-71
Wu Q, Wang X (2012) Neuronal stem cells in the central nervous system and in human
diseases. Protein & cell 3: 262-270
Xu H, Yang Y, Tang X, Zhao M, Liang F, Xu P, Hou B, Xing Y, Bao X, Fan X (2013)
Bergmann glia function in granule cell migration during cerebellum development. Molecular
neurobiology 47: 833-844
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