Centrosomes in Asymmetric Cell Division and Neocortical Development


Centrosomes play crucial roles in the homeostasis and cell cycle progression of many different cell types, and neural stem and progenitor cells (NSPCs) are not the exception. In fact, NSPCs could be among the cell types where the functions and characteristics of centrosomes are most diverse and unique. From spindle orientation to subcellular organization to primary cilium formation and beyond, centrosome functions are intimately linked to the highly polarized and dynamic architecture of NSPCs in the cerebral neocortex. This leads us to argue that centrosomes are among the organelles that most influence the cytoarchitecture of NSPCs, which translates into a decisive influence in their proliferation, differentiation and tissue and organ formation properties.

Key Concepts

  • Centrosomes are crucial for the cell and tissue biology of neural stem and progenitor cells (NSPCs).
  • Centrosomes control symmetric vs. asymmetric cell division in NSPCs.
  • Many genes implicated in neurodevelopmental disorders, such as primary microcephaly, encode centrosome proteins.
  • Centrosomes also fulfil essential nonmitotic functions, such as primary cilium formation.
  • NSPC proliferation and differentiation are influenced in diverse ways by centrosomes.

Keywords: centrosomes; asymmetric cell division; spindle orientation; primary cilium; cell polarity; cell fate; neural stem cells; radial glia; neuroepithelial cells; cortical development; neural development; neocortex

Figure 1. Centrosomes and cilia during cortical development. Major neural stem and progenitors cell (NSPC) types (blue nuclei) through the cell cycle in the developing neocortex during mid neurogenesis. Apical progenitors (APs) extend processes to connect to both the apical (ventricular) surface and the basal lamina, below the meninges. They also connect to each other via an adherens junctions belt (green‐black) and their nuclei reside in the ventricular zone (VZ). In M‐phase (M), the centrosomes (red) nucleate, position and orient the mitotic spindle. In G1, the centrosomes become the basal body of the primary cilia (yellow) and remain apical, while the nucleus initiates interkinetic (or intermitotic) nuclear migration by moving basally. The Golgi apparatus (magenta) spreads along the apical process. In S‐phase (S), the AP nucleus resides basally during chromosome and centrosome duplication. In G2, the nucleus migrates apically for the next mitosis. In AP symmetric divisions, abundant astral microtubules maintaining a mostly horizontal AP spindle. In some AP asymmetric divisions, a ciliary membrane remnant can stay associated with the mother centriole. Other progenitors derived from APs delaminate and accumulate basally. In rodents, most are neurogenic basal intermediate progenitors (bIPs) that lose apicobasal polarity. Also present, especially in mammals with a large neocortex, are basal radial glia (bRG) that delaminate from the apical surface but can still have processes and proliferate. The spindles of both these types of basal progenitors are oriented more variably, with fewer astral microtubules. Neurons (green nuclei) generated by NSPCs migrate and accumulate basally. Cells and tissue are not drawn to scale, and the basal zones and neuronal layers are not shown in detail. Fading colours indicate tissue depth.
Figure 2. The centrosome cycle in apical radial glia (aRG) of the developing mammalian neocortex. DNA staining with DAPI (cyan) and actin staining with phalloidin (white), and indirect immunofluorescence for γ‐tubulin (green) and Arl13b (red) of sections of E14.5 mouse dorsolateral telencephalon. (a) Prophase, with the axoneme and membrane of the primary cilium (ARL13B, red) and the basal body (green) that is being internalised through the apical domain (arrowhead), the apical‐most part of the aRG membrane with low actin density (white) that is delimited by adherens junctions (not shown). (b) Metaphase, The centrosomes that were at the basal body are now the poles of the mitotic spindle (arrowheads). In some divisions, the mother centrosome can retain part of the ciliary membrane (left spindle pole). (c) Late telophase/G1, the centrioles are now again part of the growing primary cilia that begin to protrude from the apical membrane of each daughter cell (arrowheads). (d) Interphase, likely G2, with a mature primary cilium dipped in cerebrospinal fluid. The scale bar is 5 µm and marks the apical side of the tissue.


Bond J, Roberts E, Mochida GH, et al. (2002) ASPM is a major determinant of cerebral cortical size. Nature Genetics 32: 316–320.

Bond J, Roberts E, Springell K, et al. (2005) A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nature Genetics 37: 353–355.

Bond J, Scott S, Hampshire DJ, et al. (2003) Protein‐truncating mutations in ASPM cause variable reduction in brain size. American Journal of Human Genetics 73: 1170–1177.

Brand AH and Livesey FJ (2011) Neural stem cell biology in vertebrates and invertebrates: more alike than different? Neuron 70: 719–729.

Cohen E and Meininger V (1987) Ultrastructural analysis of primary cilium in the embryonic nervous tissue of mouse. International Journal of Developmental Neuroscience 5: 43–51.

De Juan Romero C and Borrell V (2015) Coevolution of radial glial cells and the cerebral cortex. Glia 63: 1303–1319.

Dehay C, Kennedy H and Kosik KS (2015) The outer subventricular zone and primate‐specific cortical complexification. Neuron 85: 683–694.

Dudka D and Meraldi P (2017) Symmetry does not come for free: cellular mechanisms to achieve a symmetric cell division. Results and Problems in Cell Differentiation 61: 301–321.

Dwyer ND, Chen B, Chou SJ, et al. (2016) Neural stem cells to cerebral cortex: emerging mechanisms regulating progenitor behavior and productivity. Journal of Neuroscience 36: 11394–11401.

Faheem M, Naseer MI, Rasool M, et al. (2015) Molecular genetics of human primary microcephaly: an overview. BMC Medical Genomics 8 (Suppl. 1): S4.

Fish JL, Kosodo Y, Enard W, Paabo S and Huttner WB (2006) Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells. Proceedings of the National Academy of Sciences of the United States of America 103: 10438–10443.

Foley EA and Kapoor TM (2013) Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nature Reviews Molecular Cell Biology 14: 25–37.

Forth S and Kapoor TM (2017) The mechanics of microtubule networks in cell division. Journal of Cell Biology 216: 1525–1531.

Gai M, Bianchi FT, Vagnoni C, et al. (2016) ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules. EMBO Reports 17: 1396–1409.

Gillies TE and Cabernard C (2011) Cell division orientation in animals. Current Biology 21: R599–609.

Gilmore EC and Walsh CA (2013) Genetic causes of microcephaly and lessons for neuronal development. Wiley Interdisciplinary Reviews: Developmental Biology 2: 461–478.

Götz M and Huttner WB (2005) The cell biology of neurogenesis. Nature Reviews Molecular Cell Biology 6: 777–788.

Hertwig O (1884) Das Problem der Befruchtung und der Isotropie des Eies, eine Theory der Vererbung. Zeitschrift fur Naturwissenschaften 18: 21–23.

Homem CC, Repic M and Knoblich JA (2015) Proliferation control in neural stem and progenitor cells. Nature Review Neuroscience 16: 647–659.

Hurtado L, Caballero C, Gavilan MP, et al. (2011) Disconnecting the Golgi ribbon from the centrosome prevents directional cell migration and ciliogenesis. The Journal of Cell Biology 193: 917–933.

Huttner WB and Kosodo Y (2005) Symmetric versus asymmetric cell division during neurogenesis in the developing vertebrate central nervous system. Current Opinion in Cell Biology 17: 648–657.

Jackson AP, Eastwood H, Bell SM, et al. (2002) Identification of microcephalin, a protein implicated in determining the size of the human brain. American Journal of Human Genetics 71: 136–142.

Johansson PA, Irmler M, Acampora D, et al. (2013) The transcription factor Otx2 regulates choroid plexus development and function. Development 140: 1055–1066.

Kadowaki M, Nakamura S, Machon O, et al. (2007) N‐cadherin mediates cortical organization in the mouse brain. Developmental Biology 304: 22–33.

Kosodo Y (2012) Interkinetic nuclear migration: beyond a hallmark of neurogenesis. Cellular and Molecular Life Sciences 69: 2728–2838.

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

Kulukian A and Fuchs E (2013) Spindle orientation and epidermal morphogenesis. Philosophical Transactions of the Royal Society B: Biological Sciences 368: 20130016.

Lancaster MA and Knoblich JA (2012) Spindle orientation in mammalian cerebral cortical development. Current Opinion in Neurobiology 22: 737–746.

Lehtinen MK and Walsh CA (2011) Neurogenesis at the brain‐cerebrospinal fluid interface. Annual Review of Cell and Developmental Biology 27 (27): 653–679.

Lizarraga SB, Margossian SP, Harris MH, et al. (2010) Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors. Development 137: 1907–1917.

Loncarek J and Bettencourt‐Dias M (2018) Building the right centriole for each cell type. Journal of Cell Biology 217: 823–835.

Mahjoub MR (2013) The importance of a single primary cilium. Organogenesis 9: 61–69.

Malatesta P and Götz M (2013) Radial glia – from boring cables to stem cell stars. Development 140: 483–486.

Malatesta P, Hartfuss E and Götz M (2000) Isolation of radial glial cells by fluorescent‐activated cell sorting reveals a neuronal lineage. Development 127: 5253–5263.

Marthiens V, Rujano MA, Pennetier C, et al. (2013) Centrosome amplification causes microcephaly. Nature Cell Biology 15: 731–740.

Martinez‐Martinez MA, De Juan Romero C, Fernandez V, et al. (2016) A restricted period for formation of outer subventricular zone defined by Cdh1 and Trnp1 levels. Nature Communications 7: 11812.

Martynoga B, Drechsel D and Guillemot F (2012) Molecular control of neurogenesis: a view from the mammalian cerebral cortex. Cold Spring Harbor Perspectives in Biology 4: a008359.

Megraw TL, Sharkey JT and Nowakowski RS (2011) Cdk5rap2 exposes the centrosomal root of microcephaly syndromes. Trends in Cell Biology 21: 470–480.

Mora‐Bermudez F and Huttner WB (2015) Novel insights into mammalian embryonic neural stem cell division: focus on microtubules. Molecular Biology of the Cell 26: 4302–4306.

Mora‐Bermudez F, Matsuzaki F and Huttner WB (2014) Specific polar subpopulations of astral microtubules control spindle orientation and symmetric neural stem cell division. eLife 3: e02875.

Mora‐Bermúdez F, Turrero García M and Huttner WB (2016) Neural stem cells in cerebral cortex development. In: Pfaff NDVDW (ed) Neuroscience in the 21st Century. New York: Springer Science+Business Media.

Musacchio A and Desai A (2017) A molecular view of kinetochore assembly and function. Biology (Basel) 6: 5.

Namba T and Huttner WB (2017) Neural progenitor cells and their role in the development and evolutionary expansion of the neocortex. Wiley Interdisciplinary Reviews: Developmental Biology 6: e256.

Nano M and Basto R (2016) The Janus soul of centrosomes: a paradoxical role in disease? Chromosome Research 24: 127–144.

Nano M and Basto R (2017) Consequences of centrosome dysfunction during brain development. Advances in Experimental Medicine and Biology 1002: 19–45.

Nicholas AK, Khurshid M, Desir J, et al. (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nature Genetics 42: 1010–1014.

Nigg EA, Cajanek L and Arquint C (2014) The centrosome duplication cycle in health and disease. FEBS Letters 588: 2366–2372.

Nigg EA and Stearns T (2011) The centrosome cycle: centriole biogenesis, duplication and inherent asymmetries. Nature Cell Biology 13: 1154–1160.

Paridaen JT, Wilsch‐Brauninger M and Huttner WB (2013) Asymmetric inheritance of centrosome‐associated primary cilium membrane directs ciliogenesis after cell division. Cell 155: 333–344.

di Pietro F, Echard A and Morin X (2016) Regulation of mitotic spindle orientation: an integrated view. EMBO Reports 17: 1106–1130.

Prosser SL and Pelletier L (2017) Mitotic spindle assembly in animal cells: a fine balancing act. Nature Reviews Molecular Cell Biology 18: 187–201.

Pulvers JN, Bryk J, Fish JL, et al. (2010) Mutations in mouse Aspm (abnormal spindle‐like microcephaly associated) cause not only microcephaly but also major defects in the germline. Proceedings of the National Academy of Sciences of the United States of America 107: 16595–16600.

Sakakibara A, Ando R, Sapir T and Tanaka T (2013) Microtubule dynamics in neuronal morphogenesis. Open Biology 3 (7): 130061.

Santos N and Reiter JF (2008) Building it up and taking it down: the regulation of vertebrate ciliogenesis. Developmental Dynamics 237: 1972–1981.

Segklia A, Seuntjens E, Elkouris M, et al. (2012) Bmp7 regulates the survival, proliferation, and neurogenic properties of neural progenitor cells during corticogenesis in the mouse. PLoS One 7: e34088.

Shitamukai A, Konno D and Matsuzaki F (2011) Oblique radial glial divisions in the developing mouse neocortex induce self‐renewing progenitors outside the germinal zone that resemble primate outer subventricular zone progenitors. Journal of Neuroscience 31: 3683–3695.

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

Siller KH and Doe CQ (2009) Spindle orientation during asymmetric cell division. Nature Cell Biology 11: 365–374.

Smart IH, Dehay C, Giroud P, Berland M and Kennedy H (2002) Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cerebral Cortex 12: 37–53.

Stocker AM and Chenn A (2015) The role of adherens junctions in the developing neocortex. Cell Adhesion & Migration 9: 167–174.

Sutterlin C and Colanzi A (2010) The Golgi and the centrosome: building a functional partnership. The Journal of Cell Biology 188: 621–628.

Taverna E and Huttner WB (2010) Neural progenitor nuclei IN Motion. Neuron 67: 906–914.

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.

Taverna E, Mora‐Bermudez F, Strzyz PJ, et al. (2016) Non‐canonical features of the Golgi apparatus in bipolar epithelial neural stem cells. Scientific Reports 6: 21206.

Tolic IM (2018) Mitotic spindle: kinetochore fibers hold on tight to interpolar bundles. European Biophysics Journal 47: 191–203.

Valente EM, Rosti RO, Gibbs E and Gleeson JG (2014) Primary cilia in neurodevelopmental disorders. Nature Reviews Neurology 10: 27–36.

Wang X, Tsai JW, Imai JH, et al. (2009) Asymmetric centrosome inheritance maintains neural progenitors in the neocortex. Nature 461: 947–955.

Werner S, Pimenta‐Marques A and Bettencourt‐Dias M (2017) Maintaining centrosomes and cilia. Journal of Cell Science 130: 3789–3800.

Wilsch‐Bräuninger M, Peters J, Paridaen JTML and Huttner WB (2012) Basolateral rather than apical primary cilia on neuroepithelial cells committed to delamination. Development 139: 95–105.

Woods CG (2004) Human microcephaly. Current Opinion in Neurobiology 14: 112–117.

Woods CG, Bond J and Enard W (2005) Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. American Journal of Human Genetics 76: 717–728.

Xie Z, Hur SK, Zhao L, Abrams CS and Bankaitis VA (2018) A Golgi Lipid Signaling Pathway Controls Apical Golgi Distribution and Cell Polarity during Neurogenesis. Developmental Cell 44 (6): 725–740.

Yadav S, Puri S and Linstedt AD (2009) A primary role for Golgi positioning in directed secretion, cell polarity, and wound healing. Molecular Biology of the Cell 20: 1728–1736.

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Mora‐Bermúdez, Felipe, and Huttner, Wieland B(Sep 2018) Centrosomes in Asymmetric Cell Division and Neocortical Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021863]