Vertebrate Neurogenesis: Cell Polarity


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 (
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.


Aaku‐Saraste E, Hellwig A and Huttner WB (1996) Loss of occludin and functional tight junctions, but not ZO‐1, during neural tube closure – remodeling of the neuroepithelium prior to neurogenesis. Developmental Biology 180: 664–679.

Afonso C and Henrique D (2006) PAR3 acts as a molecular organizer to define the apical domain of chick neuroepithelial cells. Journal of Cell Science 119: 4293–4304.

Alexandre P, Reugels AM, Barker D, Blanc E and Clarke JDW (2010) Neurons derive from the more apical daughter in asymmetric divisions in the zebrafish neural tube. Nature Neuroscience 13: 673–679.

Asada N, Sanada K and Fukada Y (2007) LKB1 regulates neuronal migration and neuronal differentiation in the developing neocortex through centrosomal positioning. Journal of Neuroscience 27: 11769–11775.

Bultje RS, Castaneda‐Castellanos DR, Jan LY, et al. (2009) Mammalian Par3 regulates progenitor cell asymmetric division via notch signaling in the developing neocortex. Neuron 63: 189–202.

Cáceres A, Ye B and Dotti CG (2012) Neuronal polarity: demarcation, growth and commitment. Current Opinion in Cell Biology 24: 547–553.

Calderon de Anda F, Gärtner A, Tsai L‐H, Dotti CG and Article T (2008) Pyramidal neuron polarity axis is defined at the bipolar stage. Journal of Cell Science 121: 178–185.

Calderon de Anda F, Meletis K, Ge X, Rei D and Tsai L‐H (2010) Centrosome motility is essential for initial axon formation in the neocortex. Journal of Neuroscience 30: 10391–10406.

Chenn A and McConnell SK (1995) Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82: 631–641.

Das RM and Storey KG (2014) Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science 343: 200–204.

Del Bene F, Wehman AM, Link BA and Baier H (2008) Regulation of neurogenesis by interkinetic nuclear migration through an apical‐basal notch gradient. Cell 134: 1055–1065.

Delaunay D, Cortay V, Patti D, Knoblauch K and Dehay C (2014) Mitotic spindle asymmetry: a Wnt/PCP‐regulated mechanism generating asymmetrical division in cortical precursors. Cell Reports 6: 400–414.

Distel M, Hocking JC, Volkmann K and Köster RW (2010) The centrosome neither persistently leads migration nor determines the site of axonogenesis in migrating neurons in vivo. Journal of Cell Biology 191: 875–890.

Dong Z, Yang N, Yeo S‐Y, Chitnis A and Guo S (2012) Intralineage directional Notch signaling regulates self‐renewal and differentiation of asymmetrically dividing radial glia. Neuron 74: 65–78.

Dotti CG and Simons K (1990) Polarized sorting of viral glycoproteins to the axon and dendrites of hippocampal neurons in culture. Cell 62: 63–72.

Dubreuil V, Marzesco A‐M, Corbeil D, Huttner WB and Wilsch‐Bräuninger M (2007) Midbody and primary cilium of neural progenitors release extracellular membrane particles enriched in the stem cell marker prominin‐1. Journal of Cell Biology 176: 483–495.

Formosa‐Jordan P, Ibañes M, Ares S and Frade J‐M (2013) Lateral inhibition and neurogenesis: novel aspects in motion. International Journal of Developmental Biology 57: 341–350.

Gärtner A, Fornasiero EF, Munck S, et al. (2012) N‐cadherin specifies first asymmetry in developing neurons. EMBO Journal 31: 1893–1903.

Goehring NW (2014) PAR polarity: from complexity to design principles. Experimental Cell Research 328: 258–266.

Grego‐Bessa J, Hildebrand J and Anderson KV (2015) Morphogenesis of the mouse neural plate depends on distinct roles of cofilin 1 in apical and basal epithelial domains. Development 142: 1305–1314.

Haydar TF, Ang E and Rakic P (2003) Mitotic spindle rotation and mode of cell division in the developing telencephalon. Proceedings of the National Academy of Sciences of the United States of America 100: 2890–2895.

Higginbotham H, Eom T‐Y, Mariani LE, et al. (2012) Arl13b in primary cilia regulates the migration and placement of interneurons in the developing cerebral cortex. Developmental Cell 23: 925–938.

Higginbotham H, Guo J, Yokota Y, et al. (2013) Arl13b‐regulated cilia activities are essential for polarized radial glial scaffold formation. Nature Neuroscience 16: 1000–1007.

Homem CCF and Knoblich JA (2012) Drosophila neuroblasts: a model for stem cell biology. Development 139: 4297–4310.

Jiang J, Zhang Z‐H, Yuan X‐B and Poo M‐M (2015) Spatiotemporal dynamics of traction forces show three contraction centers in migratory neurons. Journal of Cell Biology 209: 759–774.

Kosodo Y, Röper K, Haubensak W, et al. (2004) Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO Journal 23: 2314–2324.

Kosodo Y, Toida K, Dubreuil V, et al. (2008) Cytokinesis of neuroepithelial cells can divide their basal process before anaphase. EMBO Journal 27: 3151–3163.

Kosodo Y, Suetsugu T, Suda M, et al. (2011) Regulation of interkinetic nuclear migration by cell cycle‐coupled active and passive mechanisms in the developing brain. EMBO Journal 30: 1690–1704.

Kressmann S, Campos C, Castanon I, Fürthauer M and González‐Gaitán M (2015) Directional Notch trafficking in Sara endosomes during asymmetric cell division in the spinal cord. Nature Cell Biology 17: 333–339.

Leung L, Klopper AV, Grill SW, Harris WA and Norden C (2012) Apical migration of nuclei during G2 is a prerequisite for all nuclear motion in zebrafish neuroepithelia. Development 139: 2635.

Miyata T, Okamoto M, Shinoda T and Kawaguchi A (2014) Interkinetic nuclear migration generates and opposes ventricular‐zone crowding: insight into tissue mechanics. Frontiers in Cellular Neuroscience 8: 1–11.

Mora‐Bermúdez F, Matsuzaki F and Huttner WB (2014) Specific polar subpopulations of astral microtubules control spindle orientation and symmetric neural stem cell division. eLife 3: 1–31.

Morgan JL, Dhingra A, Vardi N and Wong ROL (2006) Axons and dendrites originate from neuroepithelial‐like processes of retinal bipolar cells. Nature Neuroscience 9: 85–92.

Namba T, Funahashi Y, Nakamuta S, et al. (2015) Extracellular and intracellular signaling for neuronal polarity. Physiological Reviews 95: 995–1024.

Noctor SC, Martínez‐Cerdeño V and Kriegstein AR (2008) Distinct behaviors of neural stem and progenitor cells underlie cortical neurogenesis. Journal of Comparative Neurology 508: 28–44.

Ohata S, Aoki R, Kinoshita S, et al. (2011) Dual roles of Notch in regulation of apically restricted mitosis and apicobasal polarity of neuroepithelial cells. Neuron 69: 215–230.

Paolini A, Duchemin A‐L, Albadri S, et al. (2015) Asymmetric inheritance of the apical domain and self‐renewal of retinal ganglion cell progenitors depend on Anillin function. Development 142: 832–839.

Poggi L, Vitorino M, Masai I and Harris WA (2005) Influences on neural lineage and mode of division in the zebrafish retina in vivo. Journal of Cell Biology 171: 991–999.

Pujic Z and Malicki J (2004) Retinal pattern and the genetic basis of its formation in zebrafish. Seminars in Cell and Developmental Biology 15: 105–114.

Randlett O, Poggi L, Zolessi FR and Harris WA (2011) The oriented emergence of axons from retinal ganglion cells is directed by laminin contact in vivo. Neuron 70: 266–280.

Rasin M‐R, Gazula V‐R, Breunig JJ, et al. (2007) Numb and Numbl are required for maintenance of cadherin‐based adhesion and polarity of neural progenitors. Nature Neuroscience 10: 819–827.

Reiner O and Sapir T (2013) LIS1 functions in normal development and disease. Current Opinion in Neurobiology 23: 951–956.

Reugels AM, Boggetti B, Scheer N and Campos‐Ortega JA (2006) Asymmetric localization of Numb:EGFP in dividing neuroepithelial cells during neurulation in Danio rerio. Developmental Dynamics 235: 934–948.

Rolls MM and Doe CQ (2004) Baz, Par‐6 and aPKC are not required for axon or dendrite specification in Drosophila. Nature Neuroscience 7: 1293–1295.

Sebbagh M and Borg J‐P (2014) Insight into planar cell polarity. Experimental Cell Research 328: 284–295.

Shi SH, Jan LY and Jan YN (2003) Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3‐kinase activity. Cell 112: 63–75.

Singh S and Solecki DJ (2015) Polarity transitions during neurogenesis and germinal zone exit in the developing central nervous system. Frontiers in Cellular Neuroscience 9: 62.

Stiess M, Maghelli N, Kapitein LC, et al. (2010) Axon extension occurs independently of centrosomal microtubule nucleation. Science 327: 704–707.

Strzyz PJ, Lee HO, Sidhaye J, et al. (2015) Interkinetic nuclear migration is centrosome independent and ensures apical cell division to maintain tissue integrity. Developmental Cell 32: 203–219.

Suzuki M, Morita H and Ueno N (2012) Molecular mechanisms of cell shape changes that contribute to vertebrate neural tube closure. Development, Growth & Differentiation 54: 266–276.

Vallee RB, Seale GE and Tsai J‐W (2009) Emerging roles for myosin II and cytoplasmic dynein in migrating neurons and growth cones. Trends in Cell Biology 19: 347–355.

Wong GKW, Baudet M‐L, Norden C, Leung L and Harris WA (2012) Slit1b‐Robo3 signaling and N‐cadherin regulate apical process retraction in developing retinal ganglion cells. Journal of Neuroscience 32: 223–228.

Wu Q, Liu J, Fang A, et al. (2014) The dynamics of neuronal migration. Advances in Experimental Medicine and Biology 800: 25–36.

Xu C, Funahashi Y, Watanabe Y, et al. (2015) Radial glial cell–neuron interaction directs axon formation at the opposite side of the neuron from the contact site. Journal of Neuroscience 35: 14517–14532.

Zolessi FR, Poggi L, Wilkinson CJ, Chien C‐B and Harris WA (2006) Polarization and orientation of retinal ganglion cells in vivo. Neural Development 1: 2.

Further Reading

Barry DS, Pakan JMP and McDermott KW (2014) Radial glial cells: key organisers in CNS development. International Journal of Biochemistry and Cell Biology 46: 76–79.

Guemez‐Gamboa A, Coufal NG and Gleeson JG (2014) Primary cilia in the developing and mature brain. Neuron 82: 511–521.

Lee HO and Norden C (2013) Mechanisms controlling arrangements and movements of nuclei in pseudostratified epithelia. Trends in Cell Biology 23: 141–150.

Randlett O, Norden C and Harris WA (2011) The vertebrate retina: a model for neuronal polarization in vivo. Developmental Neurobiology 71: 567–583.

Rolls MM and Jegla TJ (2015) Neuronal polarity: an evolutionary perspective. Journal of Experimental Biology 218: 572–580.

Sanes DH, Reh TA and Harris WA (2011) Development of the Nervous System, 3rd edn. Oxford: Academic Press.

Shitamukai A and Matsuzaki F (2012) Control of asymmetric cell division of mammalian neural progenitors. Development, Growth & Differentiation 54: 277–286.

Spear PC and Erickson CA (2012) Interkinetic nuclear migration: a mysterious process in search of a function. Development, Growth & Differentiation 54: 306–316.

Taverna E, Götz M and Huttner WB (2014) The cell biology of neurogenesis: toward an understanding of the development and evolution of the neocortex. Annual Review of Cell and Developmental Biology 30: 465–502.

Yamashita M (2012) From neuroepithelial cells to neurons: changes in the physiological properties of neuroepithelial stem cells. Archives of Biochemistry and Biophysics 534: 1–7.

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