Vertebrate Neurogenesis: Cell Polarity

Abstract

Neurons originate from epithelial cells that, after proliferation and cell fate decisions, undergo a series of polarity transitions to achieve the differentiated state. The fate of neural progenitors depends on the interplay between cell cycle and neuroepithelial polarity by two main mechanisms: (1) asymmetric inheritance of cytoplasmic determinants, such as molecules of the apical adhesion complexes, and (2) interkinetic nuclear migration through gradients of signalling molecules such as Notch. Regarding cell fate, divisions can be symmetric or asymmetric. After a neuron is born, differentiation initiates with a downregulation of epithelial polarity, followed by cell detachment and migration, and the final acquisition of a neuronal morphology. All these transitions are based on extremely conserved molecular mechanisms, including the involvement of polarity protein complexes (such as the PAR3 complex) and small GTPases that mostly affect actin and microtubule dynamics. However, some important variations have been observed in different neuronal types and experimental conditions.

Key Concepts

  • Neurons are highly polarised cells that are generated from progenitors with a different kind of polarity: neuroepithelial cells.
  • The neuroepithelium is an embryonic tissue characterised by its pseudo‐stratified organisation, with a basal lamina, sub‐apical cadherin‐based adhesion complexes and an apical primary cilium.
  • The pseudo‐stratified organisation of the neuroepithelium is actively maintained by interkinetic nuclear migration, a process by which cell nuclei locate at different apicobasal positions, according to their stage in the cell cycle.
  • Interkinetic nuclear migration provides the neuroepithelium with the possibility of rapidly proliferating while maintaining a relatively reduced size in the embryo.
  • Neuroepithelial polarity and interkinetic nuclear migration favour the asymmetric distribution of signalling cues (including extracellular molecules and cytoplasmic determinants), which are essential for neurogenesis, neuronal migration and neuronal polarisation.
  • Neurons are post‐mitotic cells, which are born from a progenitor cell division that can be symmetric (generating two neurons) or asymmetric (generating one neuron and another progenitor cell).
  • After the last cell division close to the apical surface, neuroblasts must migrate to their final differentiation position, and this migration is also influenced by cell polarity cues.
  • Neuronal polarisation mechanisms have largely been studied using cell cultures, where neurons extend an axon after a period of radially symmetric, multipolar organisation.
  • In the living tissue neurons must not only polarise (form one axon and oppositely directed dendrites) but also orient properly (the axon and dendrite must be directed to the right orientation).
  • In vitro, mechanisms of neuronal polarisation rely mostly on intrinsic signals, such as the asymmetric accumulation of the PAR3 complex; in vivo, however, these intrinsic molecules are modulated by extrinsic signals such as Laminin‐1 or N‐Cadherin.

Keywords: neuroepithelium; neural progenitor; asymmetric cell division; neuronal migration; neuronal polarity

Figure 1. Not an easy task: how to make an epithelial cell into a neuron. Neuroepithelial cells, the progenitors of neurons, show a typical epithelial polarity, as they have an apical membrane separate from the basolateral membrane, apical specialisations such as a primary cilium and adhesion complexes, and contact a basal lamina at the opposite side. All the cells of the neuroepithelium are oriented parallel to each other. Neurons are also polarised, but in a different way. The two major cell domains are the axonal and somatodendritic compartments, which are specialised for a different organisation: cells orient serially to each other. Neurons do not usually come into contact with any of the tissular surfaces.
Figure 2. Interkinetic nuclear migration and neurogenesis. Neuroepithelial cells can be tightly packed thanks to the particular ability to move their nuclei alternately between the apical and basal side of the tissue. This movement is synchronised by a natural clock: the cell cycle. However, not all the cells appear to move in the same way. Evidence discussed in the article suggest that cells that move their nuclei further basally during the S phase, will undergo a neurogenic division after the next M phase. It might be possible that asymmetrically distributed signals along the apical–basal axis of the neuroepithelium are sensed by the nuclei as they migrate up and down, and are responsible for the cell decision to either stay as a dividing progenitor, or to embark in a neurogenic division. The receptor Notch, which mediates an anti‐neurogenic signal, appears as an important candidate for this role, as suggested by experimental evidence.
Figure 3. The easy way: neuroepithelial–neuronal transition in the retina. (a) In the retina, all progenitors are neuroepithelial cells, and the basal‐most neurons (retinal ganglion cells) do not have to travel long distances to reach their final destination. Once the progenitor cell undergoes a neurogenic division, one (or both) of the daughter cells will extend to the basal surface and the nucleus will simply translocate down this basal process. When the nucleus is close to its final position, the apical process will detach, bringing at its tip components of the apical end foot: cell adhesion‐related proteins and the centrosome. Neuronal differentiation (in particular, axonogenesis) will start as the cell gradually loses its epithelial polarity. For a short period, these neuroblasts look like an epithelial cell forming an axon at the opposite side of its apical domain. Genetic experiments using zebrafish and other species have unravelled some of the signals that regulate these processes. Some of these signals are cell‐extrinsic (green fonts) and others are cell‐intrinsic (orange fonts), and they may have positive or negative influence on different processes, as shown in the figure. (b–e) In vivo time‐lapse observations of the developing zebrafish retina partially supporting this model. Retinal ganglion cells are early labelled by a membrane form of red fluorescent protein (RFP) expression under the control of a specific promoter (from the transcription factor ATOH7‐encoding gene), and the apical adhesion complex and centrosome are labelled with green fluorescent protein (GFP) fused to PAR3 and Centrin, respectively. (b, d) Control situation, where the apical process is seen to detach just before axon outgrowth, bringing a PAR3 accumulation and the centrosome at its tip. (c) When SLIT1b expression is downregulated, the apical process fails to detach, while axons extend normally at the basal side. (e) Laminin α1 downregulation greatly delays axon outgrowth from retinal ganglion cells, while causing the eventual translocation of the centrosome to the cell body from the apical process. Blue arrowhead, tip of the apical process; pink arrowhead, tip of the growing axon. (b–e) Data taken and modified from (Randlett et al., 2011; Zolessi et al., 2006) © National Institutes of Health. Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/).
Figure 4. The hard way: neurogenesis in the cerebral cortex. The cortex is drawn here ‘upside down’ with respect to the most common way of representing it, to make it more comparable to an epithelium, which is always shown with the apical side up. According to a current model of neurogenesis in the mammalian cortex, at some point in development the neuroepithelium splits into two, giving rise to two types of neural progenitors: radial glial cells and basal progenitors. Radial glial cells remain with their bodies close to the ventricle, in the ventricular zone. They mostly divide vertically and undergo interkinetic nuclear migration. They maintain, then, a neuroepithelial sort of polarity. Path A shows a symmetric, proliferative division. Paths B and C show different possible types of asymmetric (albeit vertical) divisions, in which one daughter cell stays as a progenitor whereas the other one differentiates. The inheritance of the basal process by the differentiating cell determines the way of basal migration: cell locomotion (B) or nucleus translocation (C). Basal progenitors, however, detach from the apical surface of the neuroepithelium and form a new proliferative layer: the subventricular zone. They mostly divide symmetrically, giving rise to two differentiating daughter cells, and they very often show horizontal planes of cleavage (Path D). This intermediate zone and the basal progenitors are characterised by the absence of epithelial‐like polarity. When the migrating neuroblasts are going to differentiate as a pyramidal cell, they will grow their axons opposite to the direction of migration, leaving them behind as they move basally. They might even momentarily stop around the subventricular zone to initiate axon outgrowth, transiently directing their centrosome towards the base of the forming axon and changing their overall morphology. After the axon is formed, they will again direct the centrosome basally and resume migration.
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Further Reading

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Zolessi, Flavio R(Feb 2016) Vertebrate Neurogenesis: Cell Polarity. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000826.pub3]