Neurons from radial glia: the consequences of asymmetric inheritance

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Abstract

Recent work suggests that radial glial cells represent many, if not most, of the neuronal progenitors in the developing cortex. Asymmetric cell division of radial glia results in the self-renewal of the radial glial cell and the birth of a neuron. Among the proteins that direct cell fate in Drosophila melanogaster that have known mammalian homologs, Numb is the best candidate to have a similar function in radial glia. During asymmetric divisions of radial glial cells, the basal cell may inherit the radial glial fibre, while the apical cell sequesters the majority of the Numb protein. We suggest two models that make opposite predictions as to whether the radial glia or nascent neuron inherit the radial glial fiber or the majority of the Numb protein.

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.

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