PERSPECTIVES ceased at this time. Over the past 40 years, however, it has become clear that the adult brain also retains stem cells that produce neu- rons and glia throughout an animal’s life. This slow realization has challenged former preconceptions about brain development, and has provided an opportunity to explore experimentally the identity of neural stem cells and the mechanisms by which they gen- erate differentiated progeny. In particular, it offers a unique opportunity to identify cell types that function as adult stem cells and their lineage relationship to embryonic stem cells. The understanding and manipulation of neural stem cells in the embryo and the adult will have profound therapeutic implications, and will yield insight into how the brain is built and maintained throughout the life of an animal. Fundamental knowledge about stem cells in the blood, skin and other tissues has come primarily from studies in adults, in which long-term experimental intervention and transplantation are possible 1 . Similarly, exper- imental manipulations of germinal centres in the adult brain are beginning to reveal sur- prising insights. For example, stem cells in the adult vertebrate brain express molecular markers and ultrastructural characteristics of mature glia 2–5 . Given the prevailing view that glia represent a developmental endpoint, this challenges old interpretations regarding the origin of neuronal and glial cells. Another series of recent observations indicates that radial glia, long considered to be precursors of astrocytes but not neurons, have properties of embryonic stem cells 6–8 . This observation raises questions about the lineage relationship between stem cells that maintain adult brain and embryonic stem cells involved in de novo organ assembly. Here we review the glial characteristics of stem cells in the adult brain and suggest the possibility that glia-like cells might be stem cells at earlier developmental times, thus pro- viding a hypothetical continuum between the glia-like stem cells of the adult brain and the neuroepithelial cells in the embryo. Heritage of interpretation, not facts Misconceptions about the origin of neurons and glia have plagued our understanding of brain ontogeny since the early days of devel- opmental neuroscience. Soon after the description of glia as supporting cells of the nervous system, many researchers subscribed to Virchow’s assumption that glia in the cen- tral nervous system (CNS) had a mesenchy- mal origin (reviewed in REF. 9). This inference was refuted in the latter part of the nineteenth century, when histological techniques began revealing the structure of the early neural epithelium. Wilhelm His 10 examined this region and discovered that glial cells originat- ed within the CNS primordium.He incor- rectly concluded, however, that neurons and glia were produced from two separate popu- lations of progenitor cells (FIG. 1a).Rounded mitotic cells near the neural tube lumen were reported by His to be neuronal precursors and the so-called ‘spongioblasts’(elongated cells that probably correspond morphologi- cally to what we now call radial glia) were thought to produce glia. From this work emerged the dominant hypothesis that in the early neural tube, predetermined precursors produced either neurons or glia. Schaper 11 and later Sauer 12 showed that the elongated cells and the rounded mitotic cells of the early neuroepithelium were indeed the same cells at different stages of the cell cycle. Nevertheless, the idea of separate origins for neurons and glia remained heavily entrenched in the neurosciences. In reality, the complexity of For many years, it was assumed that neurons and glia in the central nervous system were produced from two distinct precursor pools that diverged early during embryonic development. This theory was partially based on the idea that neurogenesis and gliogenesis occurred during different periods of development, and that neurogenesis ceased perinatally. However, there is now abundant evidence that neural stem cells persist in the adult brain and support ongoing neurogenesis in restricted regions of the central nervous system. Surprisingly, these stem cells have the characteristics of fully differentiated glia. Neuroepithelial stem cells in the embryonic neural tube do not show glial characteristics, raising questions about the putative lineage from embryonic to adult stem cells. In the developing brain, radial glia have long been known to produce cortical astrocytes, but recent data indicate that radial glia might also divide asymmetrically to produce cortical neurons. Here we review these new developments and propose that the stem cells in the central nervous system are contained within the neuroepithelial → radial glia → astrocyte lineage. Most adult tissues retain a reservoir of self- renewing, multipotent stem cells that can generate differentiated tissue components. Until recently, the brain was thought to repre- sent an exception to this general rule. For decades, neurobiologists subscribed to the idea that neural stem cells were depleted in the perinatal brain and that neurogenesis NATURE REVIEWS | NEUROSCIENCE VOLUME 2 | APRIL 2001 | 287 A unified hypothesis on the lineage of neural stem cells Arturo Alvarez-Buylla, José Manuel García-Verdugo and Anthony D. Tramontin OPINION © 2001 Macmillan Magazines Ltd