Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism.
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.
Bush
Jeffrey O
JO
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Soriano
Philippe
P
D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000378:metabolism; D001842:Bone and Bones / Q000196:embryology*; D002478:Cells, Cultured; D003337:Corpus Callosum / Q000196:embryology; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D036387:Ephrin-B1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D005904:Glial Fibrillary Acidic Protein; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D054731:PDZ Domains / Q000502:physiology*; D036183:Receptor, EphB2 / Q000378:metabolism; D015398:Signal Transduction; D012886:Skull / Q000196:embryology
D036387:Ephrin-B1; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; D036183:Receptor, EphB2