EphB: Ephrin-B Bidirectional Signaling in Retinocollicular Mapping




Thakar, Sonal Gautam

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Retinal ganglion cell axon exit into the optic disc and formation of the optic nerve and termination in the superior colliculus is critical for integrating both the visual field and head orientation to mediate appropriate eye movement. Expression of EphB receptor tyrosine kinases and ephrin-B ligands in the visual system signify the potential role for EphB:ephrin-B bidirectional signaling in the development of the visual system. Previous studies of EphB2-/-;EphB3-/- (receptor null mutant) and EphB2lacZ/lacZ;EphB3-/- (EphB2 intracellular signaling deficient mutant) mice established that EphB acting as a ligand mediates RGC axon exit from the optic disc. Use of these compound mutants also showed EphB2 forward signaling mediates ventral RGC axon branching and formation of correct termination zones (TZ) within the medial SC. However, the molecules acting as the receptor to mediate dorsal RGC axon exit into the optic disc are unknown. Also, the EphB2 intracellular component essential for retinocollicular mapping is unknown as are the roles for EphB1, ephrin-B1, and ephrin-B2, which are also expressed in the visual system. I found that ephrin-B1 and ephrin-B2 reverse signaling has a minor role for directing RGC axon guidance to the optic nerve head. On the other hand, EphB:ephrin-B bidirectional signaling appears to play a major role in dorsoventral RGC axon retinocollicular mapping. DiI labeling of a subset of dorsal or ventral-temporal RGC axons allowed visualization of the termination zone in the superior colliculus in postnatal pups. After a comprehensive analysis of various EphB and ephrin-B null, intracellular truncation, and point mutants, that affect specific components of forward and reverse signaling, EphB:ephrin-B bidirectional signaling was found to be the key mediator of dorsoventral retinocollicular mapping. Specifically, EphB2 tyrosine kinase catalytic activity alone is critical for ventral RGC axon retinocollicular mapping and EphB1 forward signaling is crucial for ventral RGC axon retinocollicular mapping. Together, EphB1 and EphB2 are the chief mediators of ventral RGC axon retinocollicular mapping. Whereas ephrin-B1 expressed in the SC acts as a ligand to mediate ventral RGC axons, ephrin-B2 expressed in a high dorsal/low ventral gradient in the retina functions as a receptor that is important for both dorsal and ventral RGC axon retinocollicular mapping. Establishing the molecules involved with retinocollicular mapping will focus the analysis of the remaining questions pertaining to the development of the visual system.

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