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Title:
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A TrkB/EphrinA Interaction Controls Retinal Axon Branching and Synaptogenesis
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Author:
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Marler, Katharine J. M.; Becker-Barroso, Elena; Martínez, Albert; Llovera i Tomàs, Marta; Wentzel, Corinna; Poopalasundaram, Subathra; Hindges, Robert; Soriano, Eduardo; Comella i Carnicé, Joan Xavier; Drescher, Uwe
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Notes:
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Toward understanding topographically specific branching of retinal axons in their target area, we have studied the interaction between
neurotrophin receptors and members of the Eph family. TrkB and its ligand BDNF are uniformly expressed in the retina and tectum,
respectively, and exert a branch-promoting activity, whereas EphAs and ephrinAs are expressed in gradients in retina andtectum and can
mediate a suppression of axonal branching.We have identified a novelcisinteraction between ephrinA5 and TrkB on retinal ganglion cell
axons. TrkB interacts with ephrinA5 via its second cysteine-rich domain (CC2), which is necessary and sufficientfor bindingto ephrinA5.
Their functional interaction is twofold: ephrinA5 augments BDNF-promoted retinal axon branching in the absence of its activator
EphA7–Fc, whereas EphA7–Fc application abolishes branching in a local and concentration-dependent manner. The importance of TrkB
in this process is shown by the fact that overexpression of an isolated TrkB–CC2 domain interfering with the ephrinA/TrkB interaction
abolishes this regulatory interplay, whereas knockdown of TrkB via RNA interference diminishes the ephrinA5-evoked increase in
branching. The ephrinA/Trk interaction is neurotrophin induced and specifically augments the PI-3 kinase/Akt pathway generally
known to be involved in the promotion of branching. In addition, ephrinAs/TrkB modulate axon branching and also synapse formation
of hippocampal neurons. Our findings uncover molecular mechanisms of how spatially restricted axon branching can be achieved by
linking globally expressed branch-promoting with differentially expressed branch-suppressing activities. In addition, our data suggest
that growth factors and the EphA– ephrinA system interact in a way that affects axon branching and synapse development.
This work was supported by the Wellcome Trust, Biotechnology and Biological Sciences Research Council, and the Medical Research Council, as well as Ministerio de Educación y Ciencia (MEC) Grant SAF 2007-60287 and Generalitat de Catalunya to (J.C.), MEC Grant SAF2005-0171 (E.S.), Instituto de Salud Carlos III Grants PI04/2433 (A.M.) and P04/2537 (M.L.). M.L. holds a Ramon y Cajal research contract from the Spanish Ministry of Education and Science. |
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Subject(s):
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-Axon guidance
-BDNF
-Neurotrophin
-Topography |
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Rights:
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(c) Society for Neuroscience, 2008
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Document type:
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article
publishedVersion |
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Published by:
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Society for Neuroscience
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