Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism

  1. Jeffrey O. Bush and
  2. Philippe Soriano,1
  1. Program in Developmental Biology and Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA; and Department of Developmental and Regenerative Biology, Mt. Sinai School of Medicine, New York, New York 10029, USA

    Abstract

    Mutations in the ephrin-B1 gene result in craniofrontonasal syndrome (CFNS) in humans, a congenital disorder that includes a wide range of craniofacial, skeletal, and neurological malformations. In addition to the ability of ephrin-B1 to forward signal through its cognate EphB tyrosine kinase receptors, ephrin-B1 can also act as a receptor and transduce a reverse signal by either PDZ-dependent or phosphorylation-dependent mechanisms. To investigate how ephrin-B1 acts to influence development and congenital disease, we generated mice harboring a series of targeted point mutations in the ephrin-B1 gene that independently ablate specific reverse signaling pathways, while maintaining forward signaling capacity. We demonstrate that both PDZ and phosphorylation-dependent reverse signaling by ephrin-B1 are dispensable for craniofacial and skeletal development, whereas PDZ-dependent reverse signaling by ephrin-B1 is critical for the formation of a major commissural axon tract, the corpus callosum. Ephrin-B1 is strongly expressed within axons of the corpus callosum, and reverse signaling acts autonomously in cortical axons to mediate an avoidance response to its signaling partner EphB2. These results demonstrate the importance of PDZ-dependent reverse signaling for a subset of Ephrin-B1 developmental roles in vivo.

    Keywords

    Footnotes

    • 1 Corresponding author.

      E-MAIL philippe.soriano{at}mssm.edu; FAX (212) 860-9279.

    • Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1807209.

    • Supplemental material is available at http://www.genesdev.org.

      • Received March 31, 2009.
      • Accepted May 12, 2009.
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