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Developmental cell biology

The cell biology of neurogenesis

Key Points

  • Neurons in the rodent central nervous system originate from three classes of neural stem and progenitor cells — neuroepithelial cells, radial glial cells and basal progenitors. These cells undergo three main types of division — symmetric, proliferative division (neuroepithelial cells); asymmetric, neurogenic division (neuroepithelial cells and radial glial cells); and symmetric, neurogenic division (radial glial cells and basal progenitors).

  • With the onset of neurogenesis, neuroepithelial cells transform into radial glial cells. Both neuroepithelial and radial glial cells are characterized by apical–basal polarity and interkinetic nuclear migration.

  • The orientation of the cleavage plane relative to the apical–basal axis of neuroepithelial and radial glial cells is an important determinant of the type of division. Most neurogenic divisions of neuroepithelial and radial glial cells in the embryonic mouse brain involve a vertical cleavage plane (parallel to the apical–basal axis), which can either bisect the apical plasma membrane to result in a symmetric, proliferative division, or bypass the apical plasma membrane to result in an asymmetric, neurogenic division.

  • Interkinetic nuclear migration is a hallmark of neuroepithelial and radial glial cells, but its physiological significance is poorly understood. The cellular machinery that underlies this process seems to involve both microtubules and the actin cytoskeleton.

  • Concomitant with the onset and progression of neurogenesis, the length of the cell cycle of neuroepithelial and radial glial cells increases. Neuroepithelial cells that undergo neurogenic divisions have a longer cell cycle than those that undergo proliferative divisions. Moreover, in support of the cell-cycle length hypothesis, lengthening the cell cycle of neuroepithelial cells can be sufficient to switch neuroepithelial cells from proliferative to neurogenic divisions.

  • These insights into the spatial and temporal control mechanisms that operate in neural stem and progenitor cells during embryonic neurogenesis probably have implications for adult neural stem cells and adult neurogenesis.

Abstract

During the development of the mammalian central nervous system, neural stem cells and their derivative progenitor cells generate neurons by asymmetric and symmetric divisions. The proliferation versus differentiation of these cells and the type of division are closely linked to their epithelial characteristics, notably, their apical–basal polarity and cell-cycle length. Here, we discuss how these features change during development from neuroepithelial to radial glial cells, and how this transition affects cell fate and neurogenesis.

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Figure 1: Lineage trees of neurogenesis.
Figure 2: Polarized features of neuroepithelial cells, radial glial cells and basal progenitors.
Figure 3: Neurogenesis and radial glial cells.
Figure 4: Symmetric versus asymmetric division of neuroepithelial and radial glial cells.
Figure 5: SNARE control of the symmetric versus asymmetric division of neuroepithelial and radial glial cells.
Figure 6: The cell-cycle length hypothesis.

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DATABASES

Entrez Gene

ASPM

PC3

Tis21

Swiss-Prot

BLBP

EMX2

GFAP

GLAST

PAR3

prominin-1

S100β

FURTHER INFORMATION

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Glossary

MACROGLIAL CELLS

Collective term for astrocytes, oligodendrocytes and Schwann cells.

ASTROCYTES

The main type of glial cell, which has various supporting functions, including participating in the formation of the blood–brain barrier. A subpopulation of astrocytes functions as adult neural stem cells.

OLIGODENDROCYTES

Glial cells of the central nervous system that form the myelin sheath.

PROLIFERATIVE DIVISION

A division of stem or progenitor cells that results in a doubling of their number, that is, one stem cell divides into two identical stem cells or one progenitor cell divides into two identical progenitor cells.

NON-STEM-CELL PROGENITORS

Cells that are able to generate differentiated cells such as neurons but that are unable to self-renew.

PROGENITOR CELLS

Collective term for stem cells and non-stem-cell progenitors.

CELL POLARITY

The polarized organization that is characteristic of many cells, notably epithelial cells, which have a basal and an apical side.

CLEAVAGE-PLANE ORIENTATION

The orientation of the cell-division plane, which in polarized cells can be orientated parallel to the axis of cell polarity, perpendicular to this axis or at any angle in between.

INTERKINETIC NUCLEAR MIGRATION

The apical-to-basal and subsequent basal-to-apical migration of the cell nucleus during the cell cycle of epithelial, notably neuroepithelial, cells.

NEURAL PLATE

The neuroectodermal epithelium before the formation of the neural groove and neural tube.

NEURAL TUBE

The neuroectodermal epithelium after the closure of the neural groove.

TIGHT JUNCTIONS

Cell–cell junctions between epithelial cells at the apical-most end of the lateral membrane. These junctions prevent the lateral diffusion of integral membrane constituents between the apical and lateral plasma-membrane domains and the passage of extracellular compounds from the apical to the basal extracellular space and vice versa.

ADHERENS JUNCTIONS

Cell–cell junctions that exert an anchoring function and that in epithelial cells are found at the apical end of the lateral membrane just below tight junctions.

ASTROGLIAL CELLS

Term for cells that exhibit the properties of astrocytes.

GLYCOGEN GRANULES

Storage sites for glycogen in cells, notably, radial glial cells.

TELENCEPHALON

The most anterior, rostral part of the brain, which includes the cerebral cortex.

NEUROGENIC DIVISIONS

Divisions of stem or progenitor cells in which either one or both of the daughter cells are neurons.

MITOTIC SPINDLE

A microtubule-based structure that originates from the two centrosomes and that segregates the chromosomes during mitosis.

PRIMARY MICROCEPHALY

A neurodevelopmental disorder that is anatomically characterized by a small but architecturally normal brain, with the cerebral cortex showing the greatest reduction in size.

CLEAVAGE FURROW

The invagination of the plasma membrane during cell division that ultimately leads to cell fission.

CYTOKINESIS

The division of the cytoplasm, which follows nuclear division (mitosis) and completes the process of cell division.

SNARE PROTEINS

(soluble N-ethylmaleimide-sensitive fusion protein (NSF) attachment protein receptor proteins). Integral membrane proteins in various cellular membranes that interact with one another during membrane fusion.

APICAL CELL CORTEX

The apical plasma membrane plus the cytoplasmic components that are associated with it.

BASAL PROCESS

A process of neuroepithelial and radial glial cells that extends from the perikaryon (the cell body that contains the nucleus and many organelles) to the basal lamina.

SONIC HEDGEHOG

A morphogen that is involved in the patterning of the central nervous system. It carries covalently bound cholesterol at its C terminus.

LISSENCEPHALY

A malformation of the human brain in which the normal convolution of the cerebral cortex is absent, which results in a smooth cortical surface.

EPENDYMAL CELLS

Epithelial cells that line the brain ventricles and the central canal of the spinal cord.

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Götz, M., Huttner, W. The cell biology of neurogenesis. Nat Rev Mol Cell Biol 6, 777–788 (2005). https://doi.org/10.1038/nrm1739

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