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The midline is a key choice point for axon pathfinding.In binocular vertebrates (e.g., mouse and human), retinal axons diverge at the ventral diencephalon midline and only part of the retinal axons cross the midline, while in monocular vertebrates (e.g., fish), all retinal axons cross the midline and project to their contralateral targets.The molecular mechanism controlling midline crossing of retinal axons still remains a mystery.Using the zebrafish visual system as a model system, we find that two class 3 semaphorins (Sema3D and Sema3E) and their receptor neuropilinl a (Nrplla) play an important role in the midline crossing of retinal axons.In situ hybridization results reveal that at 32 hours post fertilization, when retinal axons exit the eye and start to cross the midline, Sema3D and Sema3E are expressed at the midline very near the optic ehiasm where retinal axons cross.A candidate receptor component for these two ligands, Nrpl 1 a, is highly expressed in retinal ganglion ceils at the same time when retinal axons cross the midline.In zebrafish, retinal axons project through the ehiasm and terminate in the contralateral tectum.Knocking down either Sema3D or Sema3E induces many retinal axons to project along an abnormal ipslilateral trajectory to the incorrect tectum.Misguided ipsilateral projecting axons join into the normal retinal tract originating from the contralateral eye and terminate within the incorrect rectum.Knocking down another class 3 semaphorin, Sema3A1, induces no defects in retinal axon guidance.Knocking down Nrpl1a induces similar retinal axon pathfinding errors as knocking down either Sema3D or Sema3E.Knockdown experiments further demonstrate synergetic effects of simultaneously knocking down Nrpl1a and Sema3D together or Nrp1a and Sema3E together, suggesting that both Sema3D and Sema3E function through Nrpl1a in retinal axon guidance.These findings reveal that the Sema3/Nrpl1 signaling pathway is critical for retinal axons to navigate through the midline.