Vertebrate Neurogenesis: Cell Polarity

Abstract

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.