Hermes Regulates Axon Sorting in the Optic Tract by Post-Trancriptional Regulation of Neuropilin 1

Abstract

The establishment of precise topographic maps during neural development is facilitated by the presorting of axons in the pathway before they reach their targets. In the vertebrate visual system, such topography is seen clearly in the optic tract (OT) and in the optic radiations. However, the molecular mechanisms involved in pretarget axon sorting are poorly understood. Here, we show in zebrafish that the RNA-binding protein Hermes, which is expressed exclusively in retinal ganglion cells (RGCs), is involved in this process. Using a RiboTag approach, we show that Hermes acts as a negative translational regulator of specific mRNAs in RGCs. One of these targets is the guidance cue receptor Neuropilin 1 (Nrp1), which is sensitive to the repellent cue Semaphorin 3A (Sema3A). Hermes knock-down leads to topographic missorting in the OT through the upregulation of Nrp1. Restoring Nrp1 to appropriate levels in Hermes-depleted embryos rescues this effect and corrects the axon-sorting defect in the OT. Our data indicate that axon sorting relies on Hermes-regulated translation of Nrp1.SIGNIFICANCE STATEMENT An important mechanism governing the formation of the mature neural map is pretarget axon sorting within the sensory tract; however, the molecular mechanisms involved in this process remain largely unknown. The work presented here reveals a novel function for the RNA-binding protein Hermes in regulating the topographic sorting of retinal ganglion cell (RGC) axons in the optic tract and tectum. We find that Hermes negatively controls the translation of the guidance cue receptor Neuropilin-1 in RGCs, with Hermes knock-down resulting in aberrant growth cone cue sensitivity and axonal topographic misprojections. We characterize a novel RNA-based mechanism by which axons restrict their translatome developmentally to achieve proper targeting.

Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function

“…In the olfactory system, Neuropilin-1 and its repulsive ligand, Sema-3A, are expressed on different sets of axons, which help them sort into an olfactory map within the tract ( Imai et al., 2009 ). Neuropilin-1 is also expressed in retinal axons and recent evidence suggests that it may also be involved in topographic sorting within the optic tract ( Hörnberg et al., 2016 ). It is therefore possible that CYFIP2 works downstream of Neuropilin-1 signaling.…”

Eye‐specific segregation and differential fasciculation of developing retinal ganglion cell axons in the mouse visual pathway

“…Growth cones navigating toward, through, and away from midline choice points adjust their receptor expression to continue their journey to the target (e.g., Dodd, Morton, Karagogeos, Yamamoto, & Jessell, ), but guidance molecule expression patterns on RGC axons post‐chiasm are largely unknown. Expression of guidance molecules by RGC axons within the optic tract may be regulated by local translation (Hornberg, Cioni, Harris, & Holt, ), so future experiments testing the involvement of axon order in the optic tract on targeting in the dLGN will need spatiotemporal precision in manipulations of RGC axons. That is, it will be key to selectively affect axons within the optic tract, and not those prior to the chiasm, so as to differentiate between effects on decussation versus effects on axon organization in the tract.…”

VEGF-A and neuropilin 1 (NRP1) shape axon projections in the developing CNS via dual roles in neurons and blood vessels

“…Although NRP1 was characterised initially as a cell adhesion receptor in the central nervous system ( Takagi et al, 1995 ), its precise role in axon fasciculation has been studied mainly in the peripheral nervous system, where semaphorin-induced NRP1-mediated axon-axon interactions regulate the fasciculation of sensory and motor axons ( Huettl et al, 2011 ). However, semaphorin signalling through NRP1 is not required for axon fasciculation in the optic tract ( Erskine et al, 2011 ; Hörnberg et al, 2016 ). NRP1 expression by contralateral RGC axons clearly promotes the fasciculation of these commissural axons, but whether this occurs through axon-axon interactions induced by other NRP1 ligands (such as VEGF-A) or ligand-independent NRP1 interactions remains to be established.…”