CoChat
Sign Up
Cited by 14Neurogenesis and neuroplasticity mechanismsAxon Guidance and Neuronal SignalingDevelopmental Biology and Gene Regulation

Ephrin-A2 regulates excitatory neuron differentiation and interneuron migration in the developing neocortex

Open access
Homman-Ludiye, Jihane, Kwan, William C., de Souza, Mitchell J., Rodger, Jennifer, Bourne, James A.·2017·Scientific Reports
DOI 10.1038/s41598-017-12185-xPMC PMC5603509
Open this paper in CoChat — free accountOpen PDF

Abstract

The development of the neocortex requires co-ordination between proliferation and differentiation, as well as the precise orchestration of neuronal migration. Eph/ephrin signaling is crucial in guiding neurons and their projections during embryonic development. In adult ephrin-A2 knockout mice we consistently observed focal patches of disorganized neocortical laminar architecture, ranging in severity from reduced neuronal density to a complete lack of neurons. Loss of ephrin-A2 in the pre-optic area of the diencephalon reduced the migration of neocortex-bound interneurons from this region. Furthermore, ephrin-A2 participates in the creation of excitatory neurons by inhibiting apical progenitor proliferation in the ventricular zone, with the disruption of ephrin-A2 signaling in these cells recapitulating the abnormal neocortex observed in the knockout. The disturbance to the architecture of the neocortex observed following deletion of ephrin-A2 signaling shares many similarities with defects found in the neocortex of children diagnosed with autism spectrum disorder.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-017-12185-x

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Ephrin stimulates excitatory synapses development and is closely related to neurogenesis, plasticity and learning.

    “Also, it has been shown that ephrin stimulates excitatory synapses development [127–129] and is closely related to neurogenesis, plasticity and learning [93].”

    From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [127]

    The citation [93] is attached to the claim about neurogenesis, plasticity and learning; the separate citations [127–129] accompany the synapse-development claim. The Discussion states that ephrin-A2 regulates neurogenesis, but our copy does not establish a relationship with plasticity or learning. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 55 · Cited by 14

Research works printed but not linked: 50

  1. [1]Marín O Rubenstein JLR Cell migration in the forebrain Annu Rev Neurosci 2003 26 441 483 10.1146/annurev.neuro.26.041002.131058 12626695 · DOI
  2. [2]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 7 136 144 10.1038/nn1172 14703572 · DOI · Paper page
  3. [3]Marín O Rubenstein JL A long, remarkable journey: tangential migration in the telencephalon Nat. Rev. Neurosci. 2001 2 780 790 10.1038/35097509 11715055 · DOI
  4. [4]Egger B Gold KS Brand AH Notch regulates the switch from symmetric to asymmetric neural stem cell division in the Drosophila optic lobe Development 2010 137 2981 2987 10.1242/dev.051250 20685734 PMC2926952 · DOI
  5. [5]Lah GJ Key B Dual roles of the chemorepellent axon guidance molecule RGMa in establishing pioneering axon tracts and neural fate decisions in embryonic vertebrate forebrain Devel Neurobio 2012 72 1458 1470 10.1002/dneu.22010 22275144 · DOI
  6. [6]Kaushik G Zarbalis KS Prenatal Neurogenesis in Autism Spectrum Disorders Frontiers in Chemistry 2016 4 12 10.3389/fchem.2016.00012 27014681 PMC4791366 · DOI
  7. [7]Arnold SJ The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone Genes Dev 2008 22 2479 2484 10.1101/gad.475408 18794345 PMC2546697 · DOI
  8. [9]Englund C Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex J Neurosci 2005 25 247 251 10.1523/JNEUROSCI.2899-04.2005 15634788 PMC6725189 · DOI · Paper page
  9. [10]Kriegstein AR Noctor SC Patterns of neuronal migration in the embryonic cortex Trends Neurosci 2004 27 392 399 10.1016/j.tins.2004.05.001 15219738 · DOI · Paper page
  10. [11]Rakic P Specification of cerebral cortical areas Science 1988 241 170 176 10.1126/science.3291116 3291116 · DOI · Paper page
  11. [12]Marín O Cellular and molecular mechanisms controlling the migration of neocortical interneurons Eur J Neurosci 2013 38 2019 2029 10.1111/ejn.12225 23651101 · DOI
  12. [13]Anderson SA Eisenstat DD Shi L Rubenstein JL Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes Science 1997 278 474 476 10.1126/science.278.5337.474 9334308 · DOI · Paper page
  13. [14]Gelman DM The embryonic preoptic area is a novel source of cortical GABAergic interneurons J Neurosci 2009 29 9380 9389 10.1523/JNEUROSCI.0604-09.2009 19625528 PMC6665570 · DOI · Paper page
  14. [16]Kanatani S The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain Proc Natl Acad Sci USA 2015 112 E4985 94 10.1073/pnas.1420701112 26305926 PMC4568674 · DOI
  15. [18]Rudy B Fishell G Lee S Hjerling-Leffler J Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons Devel Neurobio 2011 71 45 61 10.1002/dneu.20853 PMC3556905 21154909 · DOI · Paper page
  16. [19]Miyoshi G Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons J Neurosci 2015 35 12869 12889 10.1523/JNEUROSCI.1164-15.2015 26377473 PMC4571608 · DOI · Paper page
  17. [20]Klein R Eph/ephrin signalling during development Development 2012 139 4105 4109 10.1242/dev.074997 23093422 · DOI
  18. [21]Batlle E Wilkinson DG Molecular mechanisms of cell segregation and boundary formation in development and tumorigenesis Cold Spring Harb Perspect Biol 2012 4 a008227 a008227 10.1101/cshperspect.a008227 22214769 PMC3249626 · DOI
  19. [22]Egea J Klein R Bidirectional Eph-ephrin signaling during axon guidance Trends Cell Biol. 2007 17 230 238 10.1016/j.tcb.2007.03.004 17420126 · DOI
  20. [23]Klein R Bidirectional modulation of synaptic functions by Eph/ephrin signaling Nature Publishing Group 2009 12 15 20 19029886
  21. [24]Torii M Hashimoto-Torii K Levitt P Rakic P Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling Nature 2009 461 524 528 10.1038/nature08362 19759535 PMC2874978 · DOI
  22. [25]Dimidschstein J Ephrin-b1 controls the columnar distribution of cortical pyramidal neurons by restricting their tangential migration Neuron 2013 79 1123 1135 10.1016/j.neuron.2013.07.015 24050402 · DOI
  23. [26]Zimmer G Ephrin-A5 acts as a repulsive cue for migrating cortical interneurons Eur J Neurosci 2008 28 62 73 10.1111/j.1460-9568.2008.06320.x 18662335 · DOI
  24. [27]Zimmer G Bidirectional ephrinB3/EphA4 signaling mediates the segregation of medial ganglionic eminence- and preoptic area-derived interneurons in the deep and superficial migratory stream J Neurosci 2011 31 18364 18380 10.1523/JNEUROSCI.4690-11.2011 22171039 PMC6623906 · DOI · Paper page
  25. [28]Steinecke A Gampe C Zimmer G Rudolph J Bolz J EphA/ephrin A reverse signaling promotes the migration of cortical interneurons from the medial ganglionic eminence Development 2014 141 460 471 10.1242/dev.101691 24381199 · DOI
  26. [29]Depaepe V Ephrin signalling controls brain size by regulating apoptosis of neural progenitors Nature 2005 435 1244 1250 10.1038/nature03651 15902206 · DOI
  27. [30]North HA Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling Development 2009 136 2467 2476 10.1242/dev.034405 19542359 PMC2729353 · DOI
  28. [31]Stoner R Patches of disorganization in the neocortex of children with autism N. Engl. J. Med. 2014 370 1209 1219 10.1056/NEJMoa1307491 24670167 PMC4499461 · DOI · Paper page
  29. [32]Quinn JC Pax6 controls cerebral cortical cell number by regulating exit from the cell cycle and specifies cortical cell identity by a cell autonomous mechanism Developmental Biology 2007 302 50 65 10.1016/j.ydbio.2006.08.035 16979618 PMC2384163 · DOI
  30. [33]Bonanomi D Ret Is a Multifunctional Coreceptor that Integrates Diffusible- and Contact-Axon Guidance Signals Cell 2012 148 568 582 10.1016/j.cell.2012.01.024 22304922 PMC3286831 · DOI
  31. [34]Gerstmann K Thalamic afferents influence cortical progenitors via ephrin A5-EphA4 interactions Development 2015 142 140 150 10.1242/dev.104927 25480914 · DOI
  32. [35]Götz M Huttner WB The cell biology of neurogenesis Nat Rev Mol Cell Biol 2005 6 777 788 10.1038/nrm1739 16314867 · DOI · Paper page
  33. [36]Holmberg J Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis Genes Dev 2005 19 462 471 10.1101/gad.326905 15713841 PMC548947 · DOI
  34. [37]Verdi JM p75LNGFR regulates Trk signal transduction and NGF-induced neuronal differentiation in MAH cells Neuron 1994 12 733 745 10.1016/0896-6273(94)90327-1 7512816 · DOI
  35. [38]Hosomi S Yamashita T Aoki M Tohyama M The p75 receptor is required for BDNF-induced differentiation of neural precursor cells Biochem. Biophys. Res. Commun. 2003 301 1011 1015 10.1016/S0006-291X(03)00077-9 12589813 · DOI
  36. [39]Lim Y-S p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping Neuron 2008 59 746 758 10.1016/j.neuron.2008.07.032 18786358 PMC2677386 · DOI
  37. [40]Marler KJM A TrkB/EphrinA interaction controls retinal axon branching and synaptogenesis J Neurosci 2008 28 12700 12712 10.1523/JNEUROSCI.1915-08.2008 19036963 PMC3844751 · DOI
  38. [41]Hattori M Osterfield M Flanagan JG Regulated cleavage of a contact-mediated axon repellent Science 2000 289 1360 1365 10.1126/science.289.5483.1360 10958785 · DOI
  39. [42]Murai KK Pasquale EB ‘Eph’ective signaling: forward, reverse and crosstalk J Cell Sci 2003 116 2823 2832 10.1242/jcs.00625 12808016 · DOI
  40. [43]Letinic K Kostović I Postnatal development of calcium-binding proteins calbindin and parvalbumin in human visual cortex Cereb Cortex 1998 8 660 669 10.1093/cercor/8.7.660 9823487 · DOI
  41. [44]Brennaman, L. H. et al. Polysialylated NCAM and EphrinA/EphA Regulate Synaptic Development of GABAergic Interneurons in Prefrontal Cortex. Cereb Cortex, doi:10.1093/cercor/bhr392 (2012). PMC3513957 22275477 · DOI
  42. [45]Yu X Accelerated experience-dependent pruning of cortical synapses in ephrin-A2 knockout mice Neuron 2013 80 64 71 10.1016/j.neuron.2013.07.014 24094103 PMC3792401 · DOI
  43. [46]Jones KR Fariñas I Backus C Reichardt LF Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development Cell 1994 76 989 999 10.1016/0092-8674(94)90377-8 8137432 PMC2711896 · DOI
  44. [47]Fiumelli H Kiraly M Ambrus A Magistretti PJ Martin JL Opposite regulation of calbindin and calretinin expression by brain-derived neurotrophic factor in cortical neurons J Neurochem 2000 74 1870 1877 10.1046/j.1471-4159.2000.0741870.x 10800929 · DOI
  45. [48]Wurzman R Forcelli PA Griffey CJ Kromer LF Repetitive grooming and sensorimotor abnormalities in an ephrin-A knockout model for Autism Spectrum Disorders Behavioural brain research 2014 278C 115 128 PMC4382445 25281279
  46. [50]Krishnan, A. et al. Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder. Nat Neurosci, doi:10.1038/nn.4353 (2016). PMC5803797 27479844 · DOI
  47. [51]Huguet G Ey E Bourgeron T The genetic landscapes of autism spectrum disorders Annu Rev Genomics Hum Genet 2013 14 191 213 10.1146/annurev-genom-091212-153431 23875794 · DOI
  48. [52]Polleux F Ghosh A The slice overlay assay: a versatile tool to study the influence of extracellular signals on neuronal development Sci. STKE 2002 2002 pl9 12060788
  49. [53]Homman-Ludiye J Merson TD Bourne JA The early postnatal nonhuman primate neocortex contains self-renewing multipotent neural progenitor cells PLoS ONE 2012 7 e34383 10.1371/journal.pone.0034383 22470566 PMC3314641 · DOI
  50. [54]Homman-Ludiye J Bourne JA The guidance molecule Semaphorin3A is differentially involved in the arealization of the mouse and primate neocortex Cerebral Cortex 2014 24 2884 2898 10.1093/cercor/bht141 23709645 · DOI

Authors
Homman-Ludiye, J., Kwan, W. C., de Souza, M. J., Rodger, J., & Bourne, J. A.
Affiliations
  • Australian Regenerative Medicine Institute (AU)
  • The University of Western Australia (AU)
Corresponding author
Bourne, James A.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-09-18
Volume
7
Issue
1
Pages
11813-11813
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-017-12185-x
PMC
PMC5603509
OpenAlex
W2756122165
Cited by
14
References
55
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 5 · 2018: 2
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Monash University Research Portal (Monash University) (submittedVersion, other-oa)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
Funders
  • Australian Government
  • Stem Cells Australia
  • State Government of Victoria
  • Medical Research Council
  • National Health and Medical Research Council (1077677, 1002049, 1002258)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
ephrin-A2, Eph/ephrin signaling, neocortex development, interneuron migration, cortical lamination, diencephalon, autism spectrum disorder, ventricular zone
MeSH terms
Autism Spectrum Disorder, Animals, Cell Differentiation, Cell Movement, Child, Humans, Interneurons, Preoptic Area, Mice, Knockout, Neocortex, Ephrin-A2, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review