Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Accepted manuscripts
    • Latest complete issue
    • Issue archive
    • Archive by article type
    • Special issues
    • Subject collections
    • Sign up for alerts
  • About us
    • About Development
    • About the Node
    • Editors and Board
    • Editor biographies
    • Travelling Fellowships
    • Grants and funding
    • Journal Meetings
    • Workshops
    • The Company of Biologists
    • Journal news
  • For authors
    • Submit a manuscript
    • Aims and scope
    • Presubmission enquiries
    • Article types
    • Manuscript preparation
    • Cover suggestions
    • Editorial process
    • Promoting your paper
    • Open Access
    • Biology Open transfer
  • Journal info
    • Journal policies
    • Rights and permissions
    • Media policies
    • Reviewer guide
    • Sign up for alerts
  • Contacts
    • Contacts
    • Subscriptions
    • Advertising
    • Feedback
    • Institutional usage stats (logged-in users only)
  • COB
    • About The Company of Biologists
    • Development
    • Journal of Cell Science
    • Journal of Experimental Biology
    • Disease Models & Mechanisms
    • Biology Open

User menu

  • Log in
  • Log out

Search

  • Advanced search
Development
  • COB
    • About The Company of Biologists
    • Development
    • Journal of Cell Science
    • Journal of Experimental Biology
    • Disease Models & Mechanisms
    • Biology Open

supporting biologistsinspiring biology

Development

  • Log in
Advanced search

RSS  Twitter  Facebook  YouTube 

  • Home
  • Articles
    • Accepted manuscripts
    • Latest complete issue
    • Issue archive
    • Archive by article type
    • Special issues
    • Subject collections
    • Sign up for alerts
  • About us
    • About Development
    • About the Node
    • Editors and Board
    • Editor biographies
    • Travelling Fellowships
    • Grants and funding
    • Journal Meetings
    • Workshops
    • The Company of Biologists
    • Journal news
  • For authors
    • Submit a manuscript
    • Aims and scope
    • Presubmission enquiries
    • Article types
    • Manuscript preparation
    • Cover suggestions
    • Editorial process
    • Promoting your paper
    • Open Access
    • Biology Open transfer
  • Journal info
    • Journal policies
    • Rights and permissions
    • Media policies
    • Reviewer guide
    • Sign up for alerts
  • Contacts
    • Contacts
    • Subscriptions
    • Advertising
    • Feedback
    • Institutional usage stats (logged-in users only)
JOURNAL ARTICLES
Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina
E. Birgbauer, C.A. Cowan, D.W. Sretavan, M. Henkemeyer
Development 2000 127: 1231-1241;
E. Birgbauer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
C.A. Cowan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
D.W. Sretavan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Henkemeyer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & metrics
  • PDF
Loading

Summary

Optic nerve formation requires precise retinal ganglion cell (RGC) axon pathfinding within the retina to the optic disc, the molecular basis of which is not well understood. At CNS targets, interactions between Eph receptor tyrosine kinases on RGC axons and ephrin ligands on target cells have been implicated in formation of topographic maps. However, studies in chick and mouse have shown that both Eph receptors and ephrins are also expressed within the retina itself, raising the possibility that this receptor-ligand family mediates aspects of retinal development. Here, we more fully document the presence of specific EphB receptors and B-ephrins in embryonic mouse retina and provide evidence that EphB receptors are involved in RGC axon pathfinding to the optic disc. We find that as RGC axons begin this pathfinding process, EphB receptors are uniformly expressed along the dorsal-ventral retinal axis. This is in contrast to the previously reported high ventral-low dorsal gradient of EphB receptors later in development when RGC axons map to CNS targets. We show that mice lacking both EphB2 and EphB3 receptor tyrosine kinases, but not each alone, exhibit increased frequency of RGC axon guidance errors to the optic disc. In these animals, major aspects of retinal development and cellular organization appear normal, as do the expression of other RGC guidance cues netrin, DCC, and L1. Unexpectedly, errors occur in dorsal but not ventral retina despite early uniform or later high ventral expression of EphB2 and EphB3. Furthermore, embryos lacking EphB3 and the kinase domain of EphB2 do not show increased errors, consistent with a guidance role for the EphB2 extracellular domain. Thus, while Eph kinase function is involved in RGC axon mapping in the brain, RGC axon pathfinding within the retina is partially mediated by EphB receptors acting in a kinase-independent manner.

REFERENCES

    1. Adams R. H.,
    2. Wilkinson G. A.,
    3. Weiss C.,
    4. Diella F.,
    5. Gale N. W.,
    6. Deutsch U.,
    7. Risau W.,
    8. Klein R.
    (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13, 295–306
    OpenUrlAbstract/FREE Full Text
    1. Bartsch U.,
    2. Kirchhoff F.,
    3. Schachner M.
    (1989) Immunohistologicallocalization of the adhesion molecules L1, N-CAM, and MAG in the developing and adult optic nerve of mice. J. Comp. Neurol 284, 451–462
    OpenUrlCrossRefPubMedWeb of Science
    1. Bauch H.,
    2. Stier H.,
    3. Schlosshauer B.
    (1998) Axonal versus dendritic outgrowth is differentially affected by radial glia in discrete layers of the retina. J. Neurosci 18, 1774–1785
    OpenUrlAbstract/FREE Full Text
    1. Becker N.,
    2. Seitanidou T.,
    3. Murphy P.,
    4. Mattei M. G.,
    5. Topilko P.,
    6. Nieto M. A.,
    7. Wilkinson D. G.,
    8. Charnay P.,
    9. Gilardi-Hebenstreit P.
    (1994) Several receptor tyrosine kinase genes of the Eph family are segmentally expressed in the developing hindbrain. Mech. Dev 47, 3–17
    OpenUrlCrossRefPubMedWeb of Science
    1. Braissant O.,
    2. Foufelle F.,
    3. Scotto C.,
    4. Dauca M.,
    5. Wahli W.
    (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha,-beta, and-gamma in the adult rat. Endocrinology 137, 354–366
    OpenUrlCrossRefPubMedWeb of Science
    1. Braisted J. E.,
    2. McLaughlin T.,
    3. Wang H. U.,
    4. Friedman G. C.,
    5. Anderson D. J.,
    6. O'Leary D. D. M.
    (1997) Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system. Dev. Biol 191, 14–28
    OpenUrlCrossRefPubMedWeb of Science
    1. Brambilla R.,
    2. Bruckner K.,
    3. Orioli D.,
    4. Bergemann A. D.,
    5. Flanagan J. G.,
    6. Klein R.
    (1996) Similarities and differences in the way transmembrane-type ligands interact with the Elk subclass of Eph receptors. Mol. Cell. Neurosci 8, 199–209
    OpenUrlCrossRefPubMedWeb of Science
    1. Brittis P. A.,
    2. Lemmon V.,
    3. Rutishauser U.,
    4. Silver J.
    (1995) Unique changes of ganglion cell growth cone behavior following cell adhesion molecule perturbations: a time-lapse study of the living retina. Mol. Cell. Neurosci 6, 433–449
    OpenUrlCrossRefPubMedWeb of Science
    1. Bruckner K.,
    2. Pasquale E. B.,
    3. Klein R.
    (1997) Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275, 1640–1643
    OpenUrlAbstract/FREE Full Text
    1. Cheng H. J.,
    2. Nakamoto M.,
    3. Bergemann A. D.,
    4. Flanagan J. G.
    (1995) Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82, 371–381
    OpenUrlCrossRefPubMedWeb of Science
    1. Chung W. W.,
    2. Lagenaur C. F.,
    3. Yan Y. M.,
    4. Lund J. S.
    (1991) Developmental expression of neural cell adhesion molecules in the mouse neocortex and olfactory bulb. J. Comp. Neurol 314, 290–305
    OpenUrlCrossRefPubMedWeb of Science
    1. Connor R. J.,
    2. Menzel P.,
    3. Pasquale E. B.
    (1998) Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system. Dev. Biol 193, 21–35
    OpenUrlCrossRefPubMedWeb of Science
    1. Deiner M. S.,
    2. Kennedy T. E.,
    3. Fazeli A.,
    4. Serafini T.,
    5. Tessier-Lavigne M.,
    6. Sretavan D. W.
    (1997) Netrin-1 and DCC mediate axon guidance locally at the optic disc: loss of function leads to optic nerve hypoplasia. Neuron 19, 575–589
    OpenUrlCrossRefPubMedWeb of Science
    1. Dräger U. C.
    (1985) Birth dates of retinal ganglion cells giving rise to the crossed and uncrossed optic projections in the mouse. Proc. R. Soc. Lond. B Biol. Sci 224, 57–77
    OpenUrlCrossRefPubMed
    1. Drescher U.,
    2. Kremoser C.,
    3. Handwerker C.,
    4. Loschinger J.,
    5. Noda M.,
    6. Bonhoeffer F.
    (1995) In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 82, 359–370
    OpenUrlCrossRefPubMedWeb of Science
  1. Eph Nomenclature Committee (1997) Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 90, 403–404
    OpenUrlCrossRefPubMedWeb of Science
    1. Flanagan J. G.,
    2. Vanderhaeghen P.
    (1998) The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci 21, 309–345
    OpenUrlCrossRefPubMedWeb of Science
    1. Frisen J.,
    2. Yates P. A.,
    3. McLaughlin T.,
    4. Friedman G. C.,
    5. O'Leary D. D. M.,
    6. Barbacid M.
    (1998) Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20, 235–243
    OpenUrlCrossRefPubMedWeb of Science
    1. Gale N. W.,
    2. Holland S. J.,
    3. Valenzuela D. M.,
    4. Flenniken A.,
    5. Pan L.,
    6. Ryan T. E.,
    7. Henkemeyer M.,
    8. Strebhardt K.,
    9. Hirai H.,
    10. Wilkinson D. G.
    (1996) Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17, 9–19
    OpenUrlCrossRefPubMedWeb of Science
    1. Guillery R. W.,
    2. Lysakowski A.,
    3. Price S.
    (1985) On the distribution and probable origin of axonal bundles in the pigment epithelium of the eyecup. Brain Res 349, 293–295
    OpenUrlCrossRefPubMed
    1. Halfter W.
    (1988) Aberrant optic axons in the retinal pigment epithelium during chick and quail visual pathway development. J. Comp. Neurol 268, 161–170
    OpenUrlCrossRefPubMed
    1. Henkemeyer M.,
    2. Orioli D.,
    3. Henderson J. T.,
    4. Saxton T. M.,
    5. Roder J.,
    6. Pawson T.,
    7. Klein R.
    (1996) Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell 86, 35–46
    OpenUrlCrossRefPubMedWeb of Science
    1. Himanen J. P.,
    2. Henkemeyer M.,
    3. Nikolov D. B.
    (1998) Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2. Nature 396, 486–491
    OpenUrlCrossRefPubMedWeb of Science
    1. Holash J. A.,
    2. Pasquale E. B.
    (1995) Polarized expression of the receptor protein tyrosine kinase Cek5 in the developing avian visual system. Dev. Biol 172, 683–693
    OpenUrlCrossRefPubMedWeb of Science
    1. Holash J. A.,
    2. Soans C.,
    3. Chong L. D.,
    4. Shao H.,
    5. Dixit V. M.,
    6. Pasquale E. B.
    (1997) Reciprocal expression of the Eph receptor Cek5 and its ligand(s) in the early retina. Dev. Biol 182, 256–269
    OpenUrlCrossRefPubMedWeb of Science
    1. Holland S. J.,
    2. Gale N. W.,
    3. Mbamalu G.,
    4. Yancopoulos G. D.,
    5. Henkemeyer M.,
    6. Pawson T.
    (1996) Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 383, 722–725
    OpenUrlCrossRefPubMedWeb of Science
    1. Hornberger M. R.,
    2. Dutting D.,
    3. Ciossek T.,
    4. Yamada T.,
    5. Handwerker C.,
    6. Lang S.,
    7. Weth F.,
    8. Huf J.,
    9. Wessel R.,
    10. Logan C.
    (1999) Modulation of EphA receptor function by coexpressed ephrinA ligands on retinal ganglion cell axons. Neuron 22, 731–742
    OpenUrlCrossRefPubMedWeb of Science
    1. Kim R. Y.,
    2. Hoyt W. F.,
    3. Lessell S.,
    4. Narahara M. H.
    (1989) Superior segmental optic hypoplasia: a sign of maternal diabetes. Arch. Ophthalmol 107, 1312–1315
    OpenUrlCrossRefPubMedWeb of Science
    1. Krull C. E.,
    2. Lansford R.,
    3. Gale N. W.,
    4. Collazo A.,
    5. Marcelle C.,
    6. Yancopoulos G. D.,
    7. Fraser S. E.,
    8. Bronner-Fraser M.
    (1997) Interactions of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration. Curr. Biol 7, 571–580
    OpenUrlCrossRefPubMedWeb of Science
    1. LaVail M. M.,
    2. Battelle B. A.
    (1975) Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat. Exp. Eye Res 21, 167–192
    OpenUrlCrossRefPubMedWeb of Science
    1. Marcus R. C.,
    2. Gale N. W.,
    3. Morrison M. E.,
    4. Mason C. A.,
    5. Yancopoulos G. D.
    (1996) Eph family receptors and their ligands distribute in opposing gradients in the developing mouse retina. Dev. Biol 180, 786–789
    OpenUrlCrossRefPubMedWeb of Science
    1. Mellitzer G.,
    2. Xu Q.,
    3. Wilkinson D. G.
    (1999) Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77–81
    OpenUrlCrossRefPubMedWeb of Science
    1. Nakamoto M.,
    2. Cheng H. J.,
    3. Friedman G. C.,
    4. McLaughlin T.,
    5. Hansen M. J.,
    6. Yoon C. H.,
    7. O'Leary D. D.,
    8. Flanagan J. G.
    (1996) Topographically specific effects of ELF-1 on retinal axon guidance in vitro and retinal axon mapping in vivo. Cell 86, 755–766
    OpenUrlCrossRefPubMedWeb of Science
    1. Orioli D.,
    2. Henkemeyer M.,
    3. Lemke G.,
    4. Klein R.,
    5. Pawson T.
    (1996) Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. EMBO J 15, 6035–6049
    OpenUrlPubMedWeb of Science
    1. Ott H.,
    2. Bastmeyer M.,
    3. Stuermer C. A.
    (1998) Neurolin, the goldfish homolog of DM-GRASP, is involved in retinal axon pathfinding to the optic disk. J. Neurosci 18, 3363–3372
    OpenUrlAbstract/FREE Full Text
    1. Paschke K. A.,
    2. Lottspeich F.,
    3. Stuermer C. A.
    (1992) Neurolin, a cell surface glycoprotein on growing retinal axons in the goldfish visual system, is reexpressed during retinal axonal regeneration. J. Cell Biol 117, 863–875
    OpenUrlAbstract/FREE Full Text
    1. Silver J.,
    2. Rutishauser U.
    (1984) Guidance of optic axons in vivo by a preformed adhesive pathway on neuroepithelial endfeet. Dev. Biol 106, 485–499
    OpenUrlCrossRefPubMedWeb of Science
    1. Smith A.,
    2. Robinson V.,
    3. Patel K.,
    4. Wilkinson D. G.
    (1997) The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of branchial neural crest cells. Curr. Biol 7, 561–570
    OpenUrlCrossRefPubMedWeb of Science
    1. Stier H.,
    2. Schlosshauer B.
    (1995) Axonal guidance in the chicken retina. Development 121, 1443–1454
    OpenUrlAbstract
    1. Wang H. U.,
    2. Anderson D. J.
    (1997) Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18, 383–396
    OpenUrlCrossRefPubMedWeb of Science
    1. Wang H. U.,
    2. Chen Z. F.,
    3. Anderson D. J.
    (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753
    OpenUrlCrossRefPubMedWeb of Science
    1. Xu Q.,
    2. Alldus G.,
    3. Holder N.,
    4. Wilkinson D. G.
    (1995) Expression of truncated Sek-1 receptor tyrosine kinase disrupts the segmental restriction of gene expression in the Xenopus and zebrafish hindbrain. Development 121, 4005–4016
    OpenUrlAbstract
    1. Xu Q.,
    2. Alldus G.,
    3. Macdonald R.,
    4. Wilkinson D. G.,
    5. Holder N.
    (1996) Function of the Eph-related kinase rtk1 in patterning of the zebrafish forebrain. Nature 381, 319–322
    OpenUrlCrossRefPubMed
    1. Xu Q.,
    2. Mellitzer G.,
    3. Robinson V.,
    4. Wilkinson D. G.
    (1999) In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins. Nature 399, 267–271
    OpenUrlCrossRefPubMedWeb of Science
Previous ArticleNext Article
Back to top
Previous ArticleNext Article

This Issue

 Download PDF

Email

Thank you for your interest in spreading the word on Development.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina
(Your Name) has sent you a message from Development
(Your Name) thought you would like to see the Development web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
JOURNAL ARTICLES
Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina
E. Birgbauer, C.A. Cowan, D.W. Sretavan, M. Henkemeyer
Development 2000 127: 1231-1241;
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
JOURNAL ARTICLES
Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina
E. Birgbauer, C.A. Cowan, D.W. Sretavan, M. Henkemeyer
Development 2000 127: 1231-1241;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Alerts

Please log in to add an alert for this article.

Sign in to email alerts with your email address

Article navigation

  • Top
  • Article
  • Info & metrics
  • PDF

Related articles

Cited by...

More in this TOC section

  • Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice
  • REF-1, a protein with two bHLH domains, alters the pattern of cell fusion in C. elegans by regulating Hox protein activity
  • Centrosome migration into the Drosophila oocyte is independent of BicD and egl, and of the organisation of the microtubule cytoskeleton
Show more JOURNAL ARTICLES

Similar articles

Other journals from The Company of Biologists

Journal of Cell Science

Journal of Experimental Biology

Disease Models & Mechanisms

Biology Open

Advertisement

An interview with Swathi Arur

Swathi Arur joined the team at Development as an Academic Editor in 2020. Her lab uses multidisciplinary approaches to understand female germline development and fertility. We met with her over Zoom to hear more about her life, her career and her love for C. elegans.


Jim Wells and Hanna Mikkola join our team of Editors

We are pleased to welcome James (Jim) Wells and Hanna Mikkola to our team of Editors. Jim joins us a new Academic Editor, taking over from Gordan Keller, and Hanna joins our team of Associate Editors. Find out more about their research interests and areas of expertise.


New funding scheme supports sustainable events

As part of our Sustainable Conferencing Initiative, we are pleased to announce funding for organisers that seek to reduce the environmental footprint of their event. The next deadline to apply for a Scientific Meeting grant is 26 March 2021.


Read & Publish participation continues to grow

“I’d heard of Read & Publish deals and knew that many universities, including mine, had signed up to them but I had not previously understood the benefits that these deals bring to authors who work at those universities.”

Professor Sally Lowell (University of Edinburgh) shares her experience of publishing Open Access as part of our growing Read & Publish initiative. We now have over 150 institutions in 15 countries and four library consortia taking part – find out more and view our full list of participating institutions.


Upcoming special issues

Imaging Development, Stem Cells and Regeneration
Submission deadline: 30 March 2021
Publication: mid-2021

The Immune System in Development and Regeneration
Guest editors: Florent Ginhoux and Paul Martin
Submission deadline: 1 September 2021
Publication: Spring 2022

Both special issues welcome Review articles as well as Research articles, and will be widely promoted online and at key global conferences.


Development presents...

Our successful webinar series continues into 2021, with early-career researchers presenting their papers and a chance to virtually network with the developmental biology community afterwards. Here, Michèle Romanos talks about her new preprint, which mixes experimentation in quail embryos and computational modelling to understand how heterogeneity in a tissue influences cell rate.

Save your spot at our next session:

10 March
Time: 9:00 (GMT)
Chaired by: Thomas Lecuit

Join our mailing list to receive news and updates on the series.

Articles

  • Accepted manuscripts
  • Latest complete issue
  • Issue archive
  • Archive by article type
  • Special issues
  • Subject collections
  • Sign up for alerts

About us

  • About Development
  • About the Node
  • Editors and board
  • Editor biographies
  • Travelling Fellowships
  • Grants and funding
  • Journal Meetings
  • Workshops
  • The Company of Biologists

For authors

  • Submit a manuscript
  • Aims and scope
  • Presubmission enquiries
  • Article types
  • Manuscript preparation
  • Cover suggestions
  • Editorial process
  • Promoting your paper
  • Open Access
  • Biology Open transfer

Journal info

  • Journal policies
  • Rights and permissions
  • Media policies
  • Reviewer guide
  • Sign up for alerts

Contact

  • Contact Development
  • Subscriptions
  • Advertising
  • Feedback
  • Institutional usage stats (logged-in users only)

 Twitter   YouTube   LinkedIn

© 2021   The Company of Biologists Ltd   Registered Charity 277992