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S. L. Moseley, J. Schlessinger, H. E. Beggs; The Role of FAK, Pyk2 and Fyn in Pretarget Sorting and Topographic Mapping of the Visual System. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1882.
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© ARVO (1962-2015); The Authors (2016-present)
Precise maping of the retina to the Superior Colliculus is essential for correct visual perception. After presorting in the optic tract, counter gradients of ephrins and Eph receptors are important regulators of precise topographic mapping at the SC. However, little is known about how these cues translate into specific responses within the RGC growth cone. Non-receptor tyrosine kinases are likely candidates for regulating these growth cone responses. In this study we investigate the hypothesis that FAK, it’s close family member Pyk2, and Fyn serve as signaling nodes in RCG projections to enable precise retinotopic map formation in mice.
FAK was deleted in the retina by crossing Nestin:Cre and Six3:Cre driver lines to the Floxed-FAK allele. To investigate genetic redundancy, double mutants of the conditional FAK knockout with Pyk2 or Fyn mutants were generated. To trace retinal projections to the Superior Colliculus in vivo, DiI was microinjected into specific retinal quadrants using a picospritzer. Retinal explants were cultured adjacent to specific guidance molecules to validate in vivo findings and examine growth cone morphology.
FAK and Fyn single mutants both display major defects in pretarget sorting of axonal projections. This results in defective mapping across the medial lateral axis of the Superior Colliculus. Pyk2 mutants are also defective in medial/lateral targeting but pretarget sorting is grossly normal. All three single mutants displayed defects in targeting at sites where ephrinA/EphA gradients predominate. Additionally, FAK mutant axons do not respond to ephrinA2 as a repulsive cue in vitro. Results of synergistic interactions between FAK, Pyk2 and Fyn will be discussed.
Our results reveal a new role for FAK and Fyn as key regulators of pretarget sorting in the visual system. Additonally, FAK plays an important role in growth cone responses to ephrin-A signaling at the Superior Colliculus, likely functioning redundantly with Pyk2. These data suggest the intriguing possibility that pretarget sorting is regulated by non-receptor tyrosine kinases downstream of Eph receptors and ephrins on adjacent axons.
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