Neurons from radial glia: the consequences of asymmetric inheritance
Introduction
Mammalian cerebral cortex arises from expansion of the neural tube shortly after gastrulation, the neural plate is formed under the joint influence of signals from the node and the axial mesoderm and subsequently folds to become neural tube. During the establishment of the anterior–posterior (A–P) and dorsal–ventral (D–V) axis, no neurogenesis occurs but symmetrical cell divisions result in a dramatic expansion of the nervous system and the establishment of the neural axis [1]. From embryonic day 10 onwards, the mode of cell division within the telencephalon changes, such that increasing numbers of progenitors undergo asymmetric divisions and begin to give rise to neural progeny. By birth, the vast majority of neuronal production is complete. Just a few small populations of neural stem cells are maintained in niches that persist through adulthood. Over the past decade, numerous studies have begun to reveal both cellular and molecular mechanisms that underlie these developmental steps. In this review, we examine the different stages of central nervous system (CNS) development, focusing on cell-autonomous signals. We identify certain general principals that hold true with regard to asymmetric divisions across these developmental stages, and propose two possible but not mutually exclusive hypotheses of how asymmetric division occurs during neural development.
Section snippets
Establishment of regional pattern while in a stem cell state
The genetic evidence suggests that intrinsic determinants such as Notch and Numb are dispensable before mammalian neurogenesis; although they are later required for the proper ordering of symmetric and asymmetric cell divisions [2]. Indeed, mutants lacking genes required for specific lineal decisions, such as Notch [3] and Numb [4], develop relatively normally until the onset of neurogenesis. In contrast, extrinsic cell signals, such as Wnts, Bone morphogenetic proteins (BMPs) and Sonic
Mitotic cells provide hints concerning the regulation of the mode of division
Before considering the molecular basis of how cell division generates diversity, it is worth reviewing what is known about the neuronal progenitor cells themselves. Over the past century, developmental neurobiologists have struggled to identify the cells that give rise to neurons. Early efforts revealed that cells in mitosis were generally found apically in the ventricular zone (VZ), lining the ventricles, whereas differentiating neurons were located basally near the brain’s surface. Theories
Definitions of symmetric and asymmetric divisions
Although the terms symmetric and asymmetric are frequently used when discussing cell divisions, the precise meaning that is implied by these terms has varied widely. It is therefore helpful to establish definitions for the purpose of this review. In previous work, asymmetric divisions have been defined according to three different characteristics: first, the inclination of the plane of division with respect to an epithelial surface, second, the asymmetry of the daughter cell’s morphology, or
The implications of invertebrate neurogenesis for molecular mechanisms and models of asymmetric inheritance
Genetic studies performed on Drosophila suggest that the unequal inheritance of specific determinants is the key to intrinsically determined asymmetric cell divisions in this species. In Drosophila, in which lineages are relatively invariant, it has been possible to identify specific genes that act causally to specify asymmetric cell divisions. The discovery of mutations that perturb cell fate in Drosophila led to the cloning of a set of required genes, including Glial-cells-missing (GCM),
Adult neuronal stem cell populations
At the beginning of neurogenesis, the CNS is almost entirely composed of stem cell progenitors, whereas at the end of neurogenesis the CNS is characterized by a near absence of stem cell progenitors (Figure 4). Despite the fact that the vast majority of neurons in the brain are postmitotic by birth, it is now clear that pockets of neural stem cells persist throughout life within the hippocampus and olfactory bulb, and perhaps even more broadly 53., 54., 55., 56.. The fact that adult
Conclusions
Our understanding of neurogenesis has come a long way from the days when ‘germ cells’ and ‘spongioblasts’ were thought to mysteriously give rise to the CNS. The progression from neuroepithelium to radial glia to adult stem cell is now well characterized, as are the dynamics of the asymmetric cell divisions. Similarly, genetic studies in Drosophila have provided excellent candidate genes for exploring the molecular basis of this process in mammals. Although the precise role of these genes in
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
- •
of special interest
- ••
of outstanding interest
Acknowledgements
We thank T. Weissman and M. Götz for helpful comments.
References (62)
- et al.
Neural patterning in the vertebrate embryo
Int. Rev. Cytol.
(2001) Guidance of neurons migrating to the fetal monkey neocortex
Brain Res.
(1971)- et al.
Mitotic cycling of radial glial cells of the fetal murine cerebral wall: a combined autoradiographic and immunohistochemical study
Brain Res.
(1988) - et al.
Early divergence and changing proportions of neuronal and glial precursor cells in the primate cerebral ventricular zone
Dev. Biol.
(1983) - et al.
Asymmetric inheritance of radial glial fibers by cortical neurons
Neuron.
(2001) - et al.
Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis
Cell
(1995) - et al.
Two modes of radial migration in early development of the cerebral cortex
Nat. Neurosci.
(2001) - et al.
Glial process elongation and branching in the developing murine neocortex: a qualitative and quantitative immunohistochemical analysis
J. Comp. Neurol.
(1990) - et al.
Asymmetry and cell fate in the Drosophila embryonic CNS
Int. J. Dev. Biol.
(1998) - et al.
The glial cells missing-1 protein is essential for branching morphogenesis in the chorioallantoic placenta
Nat. Genet.
(2000)
Control of daughter cell fates during asymmetric division: interaction of Numb and Notch
Neuron.
Asymmetric segregation of the Drosophila numb protein during mitosis: facts and speculations
Cold Spring Harb. Symp. Quant. Biol.
Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis
Development
Asymmetric Numb distribution is critical for asymmetric cell division of mouse cerebral cortical stem cells and neuroblasts
Development
Stem cells in the adult mammalian central nervous system
Curr. Opin. Neurobiol.
Neurogenesis in adult primate neocortex: an evaluation of the evidence
Nat. Rev. Neurosci.
A unified hypothesis on the lineage of neural stem cells
Nat. Rev. Neurosci.
Initial patterning of the central nervous system: how many organizers?
Nat. Rev. Neurosci.
The role of notch in promoting glial and neural stem cell fates
Annu. Rev. Neurosci.
Notch1 is required for the coordinate segmentation of somites
Development
Mouse numb is an essential gene involved in cortical neurogenesis
Proc. Natl. Acad. Sci. USA
Die Neuroblasten und deren Entstehung im embryonalen Mark
Abh. Kgl. sachs. Ges. Wissensch. math phys. Kl.
Ulteriori ricerche istologiche sul cervello fetale
Rendiconti della R. Accademia dei Lincei
Mitosis in the neural tube
J Comp Neurol
An electron microscope study of cells in the matrix and intermediate laminae of the cerebral hemisphere of the 45 mm rabbit embryo
Z. Zellforsch. Mikrosk. Anat.
Cell proliferation in the neural tube: an electron microscopic and golgi analysis in the mouse cerebral vesicle
Z. Zellforsch. Mikrosk. Anat.
A study of neurogenesis in the forebrain of opossum pouch young
Z. Anat. Entwicklungsgesch
Mode of cell migration to the superficial layers of fetal monkey neocortex
J. Comp. Neurol.
Central nervous system neuronal migration
Annu. Rev. Neurosci.
Cited by (195)
Neural stem cells among glia
2020, Patterning and Cell Type Specification in the Developing CNS and PNS: Comprehensive Developmental Neuroscience, Second EditionPrenatal nicotine exposure and neuronal progenitor cells
2019, Neuroscience of Nicotine: Mechanisms and TreatmentDynamic control of neural stem cells by bHLH factors
2019, Neuroscience Research