Radial glial cell

Bipolar shaped progenitor cells of all neurons in the cerebral cortex and some glia

Radial glial cells, or radial glial progenitor cells (RGPs), are bipolar shaped progenitor cells that are responsible for producing all of the neurons in the cerebral cortex. RGPs also produce certain lineages of glia, including astrocytes and oligodendrocytes. Their cell bodies (somata) reside in the embryonic ventricular zone, which lies next to the developing ventricular system. During development, newborn neurons use radial glia as scaffolds, traveling along the radial glial fibers in order to reach their final destinations. Despite the various possible fates of the radial glial population, it has been demonstrated through clonal analysis that most radial glia have restricted, unipotent or multipotent, fates. Radial glia can be found during the neurogenic phase in all vertebrates (studied to date). The term "radial glia" refers to the morphological characteristics of these cells that were first observed: namely, their radial processes and their similarity to astrocytes, another member of the glial cell family.

Müller glia are radial glial cells that are present in the developing, as well as the adult, retina. As in the cortex, Müller glia have long processes that span the entire width of the retina, from the basal cell layer to the apical layer. However, unlike cortical radial glia, Müller glia do not appear in the retina until after the first rounds of neurogenesis have occurred. Studies suggest that Müller glia can dedifferentiate into readily dividing neural progenitors in response to injury. Since bergmann glia appear to persist in the cerebellum, and perform many of the roles characteristic of astrocytes, they have also been called "specialized astrocytes." Bergmann glial cells assist with the migration of granule cells, guiding the small neurons from the external granular layer down to the internal granular layer along their extensive radial processes. Besides their role in early development of the cerebellum, Bergmann glia are also required for synaptic pruning. Following Purkinje cell death induced by CNS injury, Bergmann glia undergo extensive proliferative changes so as to replace lost or damaged tissue in a process known as gliosis.

Radial glial cells originate from the transformation of neuroepithelial cells that form the neural plate during neurogenesis in early embryonic development. This process is mediated through the down regulation of epithelium related protein expression (such as tight junctions) and an up regulation of glial specific features such as glycogen granules, the astrocyte glutamate aspartate transporter (GLAST), the intermediate filament vimentin, and, in some instances, including humans, glial fibrillary acidic protein (GFAP).

Radial glia are now recognized as key progenitor cells in the developing nervous system. During the late stages of neurogenesis, radial glial cells divide asymmetrically in the ventricular zone, generating a new radial glial cell, as well as a postmitotic neuron or an intermediate progenitor (IPC) daughter cell. Intermediate progenitor cells then divide symmetrically in the subventricular zone to generate neurons. Radial glial cells show high levels of calcium transient activity, which is transmitted between RGCs in the ventricular zone and along the radial fibers bidirectionally to/from the cortical plate. The calcium activity is thought to promote RGC proliferation and could be involved in radial communication before synapses are present in the brain. Additionally, recent evidence suggests that cues from the external sensory environment can also influence the proliferation and neural differentiation of radial glia. At the conclusion of cortical development, most radial glia lose their attachment to the ventricles, and migrate towards the surface of the cortex, where, in mammals, most will become astrocytes during the process of gliogenesis. Recently, radial glia that exclusively generate upper layer cortical neurons have also been discovered.

The best characterized and first widely accepted function of radial glia is their role as scaffolds for neuronal migration in the cerebral and cerebellar cortexes. This role can be easily visualized using the electron microscope or high resolution time lapse microscopy, through which neurons can be seen tightly wrapped around radial glia as they travel upwards through the cortex.

As radial glia serve as the primary neural and glial progenitors in the brain, as well as being crucial for proper neuronal migration, defects in radial glial function can have profound effects in the development of the nervous system. Mutations in either Lis1 or Nde1, essential proteins for radial glial differentiation and stabilization, cause the associated neurodevelopmental diseases Lissencephaly and microlissencephaly (which literally translate to “smooth brain”). Patients with these diseases are characterized by a lack of cortical folds (sulci and gyri) and reduced brain volume. Extreme cases of Lissencephaly cause death a few months after birth, while patients with milder forms may experience mental retardation, difficulty balancing, motor and speech deficits, and epilepsy. Epidemiological evidence indicates infection of the embryo within the first two trimesters of pregnancy has potential to cause fetal birth defects and microcephaly, possibly due to the death of progenitor cells. Further, mutations in microcephaly associated genes which encode proteins such as WDR62 can lead to radial glial depletion during brain development which ultimately leads to a smaller brain size and mental disabilities.

Camillo Golgi, using his silver staining technique (later deemed the Golgi method), first described radially oriented cells spanning from the central canal to the outer surface of the embryonic chick spinal cord, in 1885. Using the Golgi method, Giuseppe Magini then studied the mammalian fetal cerebral cortex in 1888, confirming the similar presence of elongated radial cells in the cortex (also described by Kölliker just before him), and observing “various varicosities or swellings” on the radial fibers. Intrigued, Magini also observed that the size and number of these varicosities increased later in development, and were absent in the adult nervous system. Based on these findings, Magini then hypothesized that these varicosities could be developing neurons. Using a combination Golgi and hematoxylin staining method, Magini was able to identify these varicosities as cells, some of which were very closely associated with the radial fibers. Additional early works that were important in elucidating the identity and function of radial glia, were completed by Ramón y Cajal, who first suggested that the radial cells were a type of glia through their similarities to astrocytes; and Wilhelm His, who also proposed the idea that growing axons may use radial cells for orientation and guidance during development. Despite the initial period of interest in radial glia, little additional information was learned about these cells until the electron microscope and immunohistochemistry became available some 60 years later.