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Event: 2203

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Decreased proliferation of cortical neural progenitor cells

Short name
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Decreased proliferation of cortical NPCs
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Biological Context

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Level of Biological Organization

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
RAR agonism during neurodevelopment leading to impaired learning and memory KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite
RAR agonism during neurodevelopment leading to microcephaly KeyEvent Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI

Life Stages

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Sex Applicability

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Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Cell proliferation refers to the process of increasing the total number of cells through growth and division (Homem et al., 2015). In tissues, the rate of proliferation is influenced by multiple factors such as the initial pool of progenitor cells, the number and frequency of divisions they undergo, and the proportion of daughter cells that retain the proliferative potential (Homem et al., 2015).

During brain development, the regulation of cell proliferation is important for the production of all cell types, including neurons which assemble into functional neural circuits (Ohnuma and Harris, 2003). Neurons in the brain originate from the neuroepithelial cell (NEC) population initially undergoing symmetric, self-renewing divisions at the luminal surface of the neural tube (Malatesta et al., 2008). NECs can be identified by expression of Sox2 and Nestin, or apical surface markers like Occludin and Zonula Occludens 1 (ZO-1) (Götz and Huttner, 2005). Subsequently, NECs undergo asymmetric divisions, generating radial glial cells (RGCs), a proliferative cell population which represents the main pool of neural progenitors for all regions of the developing brain (Anthony et al., 2004; Malatesta et al., 2008).  RGCs continue to express Nestin, and additionally express glial markers such as the glutamate transporter GLAST, glial fibrillary acidic protein (GFAP) and brain-lipid-binding protein (BLBP) (Anthony et al., 2004; Götz and Huttner, 2005).

During neocortical histogenesis, RGCs divide symmetrically and asymmetrically. The majority of asymmetric divisions are neurogenic, whereby RGC division yields a new RGC and a postmitotic neuron (Noctor et al., 2004). Other asymmetric divisions generate intermediate progenitors, which can then divide symmetrically to produce two neurons (Noctor et al., 2004). Following neurogenesis, a fraction of RGCs transition to gliogenesis to give rise to glial cells, including astrocytes and oligodendrocytes, whereas the remaining RGCs exit the cell cycle through a terminal neurogenic division (Gao et al., 2014).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Proliferation in neural progenitor cells can be measured using various experimental approaches.

1. Incorporation of thymidine analogues

In preparation of cell division, eukaryotic cells duplicate their genetic material. During this process, the nucleoside subunits inserted into the newly synthesised DNA can be labelled and quantified, thus providing a means to measure cell proliferation. This is typically done by using various analogues of the nucleoside thymidine, such as tritiated thymidine (3H-thymidine), bromodeoxyuridine (BrdU) or 5-ethynyl-2'-deoxyuridine (EdU) (Cavanagh et al., 2011). These thymidine analogues can be detected by autoradiography or scintillation techniques (3H-thymidine), immunofluorescence (BrdU) and reaction with fluorescent azides (EdU) (Cavanagh et al., 2011). These approaches have been successfully applied to quantify NPC proliferation (Koch et al., 2022; Liu et al., 2018; Wu et al., 2009; Wang et al., 2005).

2. Immunostaining or flow cytometric analysis of proteins associated with the cell cycle, such as cell cycle regulators or proteins with important functions during mitosis. 


3. In-situ hybridization (ISH) techniques can be applied to quantify mRNA transcripts of various markers of cycling NPCs (Yeh et al., 2013).

4. Time-lapse Imaging: Live-cell imaging techniques allow tracking of neural progenitor cells over time and assessment of their proliferation rates and patterns (Bestman et al., 2012; Keenan et al., 2010).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help


List of the literature that was cited for this KE description. More help

1.                         Homem CC, Repic M, Knoblich JA. Proliferation control in neural stem and progenitor cells. Nat Rev Neurosci. 2015;16(11):647-59.

2.                         Ohnuma S, Harris WA. Neurogenesis and the cell cycle. Neuron. 2003;40(2):199-208.

3.                         Malatesta P, Appolloni I, Calzolari F. Radial glia and neural stem cells. Cell Tissue Res. 2008;331(1):165-78.

4.                         Götz M, Huttner WB. The cell biology of neurogenesis. Nat Rev Mol Cell Biol. 2005;6(10):777-88.

5.                         Anthony TE, Klein C, Fishell G, Heintz N. Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron. 2004;41(6):881-90.

6.                         Noctor SC, Martínez-Cerdeño V, Ivic L, Kriegstein AR. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci. 2004;7(2):136-44.

7.                         Gao P, Postiglione MP, Krieger TG, Hernandez L, Wang C, Han Z, et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex. Cell. 2014;159(4):775-88.

8.                         Cavanagh BL, Walker T, Norazit A, Meedeniya AC. Thymidine analogues for tracking DNA synthesis. Molecules. 2011;16(9):7980-93.

9.                         Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133(4):1710-5.

10.                       Zhou X, Zhong S, Peng H, Liu J, Ding W, Sun L, et al. Cellular and molecular properties of neural progenitors in the developing mammalian hypothalamus. Nat Commun. 2020;11(1):4063.

11.                       Strzalka W, Ziemienowicz A. Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation. Ann Bot. 2011;107(7):1127-40.

12.                       Essers J, Theil AF, Baldeyron C, van Cappellen WA, Houtsmuller AB, Kanaar R, et al. Nuclear dynamics of PCNA in DNA replication and repair. Mol Cell Biol. 2005;25(21):9350-9.

13.                       Kurki P, Vanderlaan M, Dolbeare F, Gray J, Tan EM. Expression of proliferating cell nuclear antigen (PCNA)/cyclin during the cell cycle. Exp Cell Res. 1986;166(1):209-19.

14.                       Arai Y, Pulvers JN, Haffner C, Schilling B, Nüsslein I, Calegari F, et al. Neural stem and progenitor cells shorten S-phase on commitment to neuron production. Nat Commun. 2011;2:154.

15.                       Kearsey SE, Labib K. MCM proteins: evolution, properties, and role in DNA replication. Biochim Biophys Acta. 1998;1398(2):113-36.

16.                       Fauser M, Weselek G, Hauptmann C, Markert F, Gerlach M, Hermann A, et al. Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain. Front Neuroanat. 2020;14:558435.

17.                       Dougherty JD, Garcia AD, Nakano I, Livingstone M, Norris B, Polakiewicz R, et al. PBK/TOPK, a proliferating neural progenitor-specific mitogen-activated protein kinase kinase. J Neurosci. 2005;25(46):10773-85.

18.                       Sun D, Sun XD, Zhao L, Lee DH, Hu JX, Tang FL, et al. Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior. Cell Death Dis. 2018;9(1):8.

19.                       Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, et al. Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 1997;106(6):348-60.

20.                       Xing L, Kalebic N, Namba T, Vaid S, Wimberger P, Huttner WB. Serotonin Receptor 2A Activation Promotes Evolutionarily Relevant Basal Progenitor Proliferation in the Developing Neocortex. Neuron. 2020;108(6):1113-29.e6.

21.                       Fietz SA, Namba T, Kirsten H, Huttner WB, Lachmann R. Signs of Reduced Basal Progenitor Levels and Cortical Neurogenesis in Human Fetuses with Open Spina Bifida at 11-15 Weeks of Gestation. J Neurosci. 2020;40(8):1766-77.

22.                       Hashimoto-Torii K, Torii M, Fujimoto M, Nakai A, El Fatimy R, Mezger V, et al. Roles of heat shock factor 1 in neuronal response to fetal environmental risks and its relevance to brain disorders. Neuron. 2014;82(3):560-72.

23.                       Kim KC, Go HS, Bak HR, Choi CS, Choi I, Kim P, et al. Prenatal exposure of ethanol induces increased glutamatergic neuronal differentiation of neural progenitor cells. J Biomed Sci. 2010;17(1):85.

24.                       Yeh CW, Kao SH, Cheng YC, Hsu LS. Knockdown of cyclin-dependent kinase 10 (cdk10) gene impairs neural progenitor survival via modulation of raf1a gene expression. J Biol Chem. 2013;288(39):27927-39.

25.                       Bestman JE, Lee-Osbourne J, Cline HT. In vivo time-lapse imaging of cell proliferation and differentiation in the optic tectum of Xenopus laevis tadpoles. J Comp Neurol. 2012;520(2):401-33.

26.                       Keenan TM, Nelson AD, Grinager JR, Thelen JC, Svendsen CN. Real time imaging of human progenitor neurogenesis. PLoS One. 2010;5(10):e13187.