The Intracellular Domain of EPHB1 Is Required for Axon Pathfinding at the Optic Chiasm and Corpus Callosum




Chenaux, George

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This dissertation presents evidence of the importance of EphB1 mediated signaling in retinal and callosal axons while attempting to reach their targets. EphB receptor tyrosine kinases direct axonal pathfinding through interactions with ephrin-B proteins following axon-cell contact. Since EphB:ephrin-B binding leads to bidirectional signals, the contributions of signaling into the Eph-expressing cell (forward signaling) or the ephrin-expressing cell (reverse signaling) cannot be assigned using traditional protein-null alleles. To determine if EphB1 is functioning as a receptor during axon pathfinding, I created a new knock-in mutant mouse, EphB1 T-lacZ, that expresses an intracellular-truncated EphB1-β-gal fusion protein from the endogenous locus. As in the EphB1 -/-protein-null animals, the EphB1 T-lacZ/T-lacZ homozygotes fail to form the ipsilateral projecting subpopulation of retinal ganglion cell (RGC) axons. This indicates that forward signaling through the intracellular domain of EphB1 is required for proper axon pathfinding of RGC axons at the optic chiasm. Further analysis of other EphB and ephrin-B mutant mice shows that EphB1 is the preferred receptor of both ephrin-B1 and ephrin-B2 in mediating axon guidance at the optic chiasm despite the coexpression of EphB2 in the same ipsilaterally projecting RGC axons.
In addition to analyzing the axon pathfinding defect at the optic chiasm, the EphB1 T-lacZ mice were also used to analyze another phenotype associated with EphB1 -/-protein-null animals, a failure to properly form a corpus callosum. I will show that the intracellular domains of EphB1 and EphB2 are important for the guidance of callosal axons across the midline during the formation of the corpus callosum. However, opposite to the above mentioned optic chiasm phenotype, these animals have axons that fail to project contralaterally choosing to remain on the ipsilateral hemisphere.

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