Semaphorin-6D and Plexin-A1 Act in a Non-Cell-Autonomous Manner to Position and Target Retinal Ganglion Cell Axons.

Semaphorins and Plexins form ligand/receptor pairs that are crucial for a wide range of developmental processes from cell proliferation to axon guidance. The ability of semaphorins to act both as signaling receptors and ligands yields a multitude of responses. Here, we describe a novel role for Semaphorin-6D (Sema6D) and Plexin-A1 in the positioning and targeting of retinogeniculate axons. In Plexin-A1 or Sema6D mutant mice of either sex, the optic tract courses through, rather than along, the border of the dorsal lateral geniculate nucleus (dLGN), and some retinal axons ectopically arborize adjacent and lateral to the optic tract rather than defasciculating and entering the target region. We find that Sema6D and Plexin-A1 act together in a dose-dependent manner, as the number of the ectopic retinal projections is altered in proportion to the level of Sema6D or Plexin-A1 expression. Moreover, using retinal in utero electroporation of Sema6D or Plexin-A1 shRNA, we show that Sema6D and Plexin-A1 are both required in retinal ganglion cells for axon positioning and targeting. Strikingly, nonelectroporated retinal ganglion cell axons also mistarget in the tract region, indicating that Sema6D and Plexin-A1 can act non-cell-autonomously, potentially through axon-axon interactions. These data provide novel evidence for a dose-dependent and non-cell-autonomous role for Sema6D and Plexin-A1 in retinal axon organization in the optic tract and dLGN.SIGNIFICANCE STATEMENT Before innervating their central brain targets, retinal ganglion cell axons fasciculate in the optic tract and then branch and arborize in their target areas. Upon deletion of the guidance molecules Plexin-A1 or Semaphorin-6D, the optic tract becomes disorganized near and extends within the dorsal lateral geniculate nucleus. In addition, some retinal axons form ectopic aggregates within the defasciculated tract. Sema6D and Plexin-A1 act together as a receptor-ligand pair in a dose-dependent manner, and non-cell-autonomously, to produce this developmental aberration. Such a phenotype highlights an underappreciated role for axon guidance molecules in tract cohesion and appropriate defasciculation near, and arborization within, targets.

Retinal axon guidance at the midline: Chiasmatic misrouting and consequences.

The visual representation of the outside world relies on the appropriate connectivity between the eyes and the brain. Retinal ganglion cells are the sole neurons that send an axon from the retina to the brain, and thus the guidance decisions of retinal axons en route to their targets in the brain shape the neural circuitry that forms the basis of vision. Here, we focus on the choice made by retinal axons to cross or avoid the midline at the optic chiasm. This decision allows each brain hemisphere to receive inputs from both eyes corresponding to the same visual hemifield, and is thus crucial for binocular vision. In achiasmatic conditions, all retinal axons from one eye project to the ipsilateral brain hemisphere. In albinism, abnormal guidance of retinal axons at the optic chiasm leads to a change in the ratio of contralateral and ipsilateral projections with the consequence that each brain hemisphere receives inputs primarily from the contralateral eye instead of an almost equal distribution from both eyes in humans. In both cases, this misrouting of retinal axons leads to reduced visual acuity and poor depth perception. While this defect has been known for decades, mouse genetics have led to a better understanding of the molecular mechanisms at play in retinal axon guidance and at the origin of the guidance defect in albinism. In addition, fMRI studies on humans have now confirmed the anatomical and functional consequences of axonal misrouting at the chiasm that were previously only assumed from animal models. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 844-860, 2017.