*Institute for Stem Cell Research, GSF — National Research Center for Environment and Health, Ingolstädter Landstrasse 1, D-85764 Neuherberg/Munich, Germany.‡Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, D-01307 Dresden, Germany.e-mails: [email protected]; [email protected]:10.1038/nrm1739MACROGLIAL CELLSCollective term for astrocytes, oligodendrocytes and Schwann cells.ASTROCYTESThe 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.THE CELL BIOLOGY OF NEUROGENESISMagdalena Götz* and Wieland B. Huttner‡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.During development, neural stem cells give rise to all the neurons of the mammalian central nervous system (CNS). They are also the source of the two types of MACROGLIAL CELL in the CNS — ASTROCYTES and OLIGODENDROCYTES1–5. Usually, two criteria are applied to define a cell as a stem cell — self-renewal, ideally for an unlimited number of cell divisions, and multipotency, that is, the ability to give rise to numerous types of differentiated cell. However, as it is not clear to what extent multipotent stem cells exist during the develop-ment of the CNS1–3,5–16, we use the term stem cells here to describe neural cells that are self-renewing, but not necessarily for an unlimited number of cell divisions, and that might be multipotent or unipotent.The self-renewal of neural stem cells can occur either by symmetric cell divisions, which generate two daughter cells with the same fate, or by asymmetric cell divisions, which generate one daughter cell that is identical to the mother cell and a second, different cell type. Notably, during development, neuroepithelial cells, which can be considered stem cells, first undergo symmetric, PROLIFERATIVE DIVISIONS, each of which generates two daughter stem cells17,18. These divisions are followed by many asym-metric, self-renewing divisions, each of which generates a daughter stem cell plus a more differentiated cell such as a NONSTEMCELL PROGENITOR or a neuron (FIG. 1). Neural non-stem-cell progenitors typically undergo symmetric, differentiating divisions, each of which generates two neurons — terminally differentiated, postmitotic cells. These types of division were first deduced from retroviral cell-lineage-tracing experiments19–25 and were subse-quently shown directly in live time-lapse observations with brain slices26–31 and isolated cells in vitro32–37.This review mainly discusses the cell-biological basis of the symmetric versus asymmetric division of neural stem and PROGENITOR CELLS, concentrating on the devel-oping CNS of rodents (from which most of the available data were derived) and focusing on issues such as CELL POLARITY, CLEAVAGEPLANE ORIENTATION, apical cell constitu-ents, INTERKINETIC NUCLEAR MIGRATION and cell-cycle length. Before addressing these issues, we first briefly describe the main categories of neural stem and progenitor cells, as well as some of their basic cell-biological features.Neural stem and progenitor cellsNeuroepithelial cells. Before neurogenesis, the NEURAL PLATE and NEURAL TUBE are composed of a single layer of cells, neuroepithelial cells, which form the neuroepi-thelium. The neuroepithelium looks layered (‘pseu-dostratified’), because the nuclei of neuroepithelial cells migrate up and down the apical–basal axis dur-ing the cell cycle (interkinetic nuclear migration; see below and FIG. 2a). Neuroepithelial cells show typical epithelial features and are highly polarized along their apical–basal axis, as is obvious from the organization of their plasma membrane38,39 (FIG. 2a). Certain trans-membrane proteins such as prominin-1 (CD133) are selectively found in the apical plasma membrane40,41; DEVELOPMENTAL CELL BIOLOGY NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 6 | OCTOBER 2005 | 777REVIEWSSymmetric, proliferative divisionNENENEN NNNNNNENENE Asymmetric, neurogenic divisionRGRGRG Asymmetric, neurogenic divisionRG Symmetric, neurogenic divisionSymmetric, proliferative division Asymmetric, differentiative division Asymmetric, differentiative divisionBPN NBPN NBPN NBP Symmetric, differentiative division Symmetric, neurogenic division Symmetric, neurogenic divisionSymmetric, neurogenic divisionSymmetric, neurogenic divisionabOLIGODENDROCYTESGlial cells of the central nervous system that form the myelin sheath.PROLIFERATIVE DIVISIONA 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 PROGENITORSCells that are able to generate differentiated cells such as neurons but that are unable to self-renew.PROGENITOR CELLSCollective term for stem cells and non-stem-cell progenitors.CELL POLARITYThe polarized organization that is characteristic of many cells, notably epithelial cells, which have a basal and an apical side.CLEAVAGEPLANE ORIENTATIONThe 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.TIGHT JUNCTIONS and ADHERENS JUNCTIONS are present at the most apical end of the lateral plasma membrane42–44; and receptors for basal lamina constituents such as integrin α6 are concentrated in the basal plasma membrane, which contacts the basal lamina39. The apical–basal polarity of neuroepithelial cells seems to require the integrity of adherens junctions. Knocking out the adherens-junction-associated protein afadin, also known as AF6, perturbs the polarized organiza-tion of these cells43.Radial glial cells. With the generation of neurons, the neuroepithelium transforms into a tissue with numer-ous cell layers, and the layer that lines