Segregation of Ipsilateral Retinal Ganglion Cell Axons at the Optic Chiasm Requires the Shh Receptor Boc

Abstract

The pattern of contralaterally and ipsilaterally projecting retinal ganglion cell (RGC) axons at the optic chiasm is essential for the establishment of binocular vision. Contralateral axons cross the chiasm midline as they progress from the optic nerve to the optic tract. In contrast, ipsilateral axons deviate from the chiasm and continue in the ipsilateral optic tract, avoiding the chiasm midline. The molecular mechanism underlying this phenomenon is not completely understood. Here we show that the Sonic Hedgehog (Shh) receptor Boc is enriched in ipsilateral RGCs of the developing retina. Together with the presence of Shh at the midline, this complementary expression pattern led us to hypothesize that Shh might repel ipsilateral RGC axons at the chiasm. Consistent with this hypothesis, we found that only Boc-positive RGC axons retract in vitro in response to Shh and that this response is lost in Boc mutant RGCs. In vivo, we show that Boc is required for the normal segregation of ipsilateral axons at the optic chiasm and, conversely, that Boc expression in contralateral RGCs prevents their axons from crossing the optic chiasm. Together, these results suggest that Shh repels ipsilateral RGC axons at the optic chiasm via its receptor Boc. This work identifies a novel molecular pathway required for the segregation of axons at the optic chiasm.

Gas1 is a receptor for sonic hedgehog to repel enteric axons

“…Because Gas1 mutants have a compromised floorplate, which may indirectly affect the commissural trajectory, its role in commissural axon attraction requires clarification. On the other hand, Shh at the optic chiasm acts through Boc to induce retraction of ventro-temporal retinal axons (35,36). Cdo is expressed in retinal neurons but has no apparent roles (36), whereas Gas1 is required earlier to pattern the neural retina (37).…”

“…On the other hand, Shh at the optic chiasm acts through Boc to induce retraction of ventro-temporal retinal axons (35,36). Cdo is expressed in retinal neurons but has no apparent roles (36), whereas Gas1 is required earlier to pattern the neural retina (37). Furthermore, Gas1, Boc, and Cdo act cooperatively in several Hh-mediated embryonic patterning events, but they also show unique prevalence for each specific compound mutant phenotype depending on dosage and expression (38,39).…”

Heparan Sulfate Sugar Modifications Mediate the Functions ofSlitsand Other Factors Needed for Mouse Forebrain Commissure Development

“…One candidate is the secreted morphogen Shh which can guide RGC axons and whose signaling activity depends on HSPGs (Trousse et al, 2001;Grobe et al, 2005;Dierker et al, 2009a,b). Disrupting Shh or its receptor BOC produces increased ectopic RGC axon navigation into the contralateral optic nerve reminiscent of the Hs6st1 Ϫ/Ϫ phenotype (Sánchez-Camacho and Bovolenta, 2008;Fabre et al, 2010).…”

brother of cdo (umleitung) is cell-autonomously required for Hedgehog-mediated ventral CNS patterning in the zebrafish

“…This suggests that boc might be a candidate gene for human HPE (Ming and Muenke, 1998). Despite the fact that Boc is known to play a direct role in axon guidance of mouse commissural neurons (Okada et al, 2006) and retinal ganglion cells (Fabre et al, 2010), retinal axon guidance defects in uml(boc) mutants (Fig. 1) are probably indirect.…”

“…Boc acts as a receptor for Shh and mediates commissural axon guidance in the spinal cord (Okada et al, 2006). Boc is also required to repel retinal ganglion cell (RGC) growth cones from regions expressing Shh in the mouse forebrain (Fabre et al, 2010) and for the proper formation of ventrally projecting axon tracts in the zebrafish brain (Connor et al, 2005).…”