Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm.

Retinal ganglion cell (RGC) axons from each eye execute a series of maneuvers as they converge on the ventral surface of the brain at the optic chiasm for sorting into the optic tracts. Heparan sulfate proteoglycans (HSPGs) are extracellular glycoproteins involved in cell-surface interactions. HSPGs exhibit massive structural diversity, conferred partly by extensive post-translational modification including differential sulfation. Here we examine the roles of HSPG sulfation in RGC axon guidance at the chiasm. We identified different axon navigation phenotypes in two heparan sulfate sulfotransferase (Hst) mutant embryos, Hs2st-/- and Hs6st1-/-, each lacking an enzyme that catalyzes a particular HSPG modification. Hs2st-/- embryos display axon disorganization at the chiasm. Hs6st1-/- embryos exhibit prolific inter-retinal innervation. We show that RGCs express Hs2st and Hs6st1 and that navigation errors made by their axons coincide with regions of high Hs2st and/or Hs6st1 expression at the chiasm. Slit proteins are expressed at particular locations in the retina and around the chiasm and are normally deployed to prevent axons entering inappropriate territories. We show that Hs2st and/or Hs6st1 expression coincides with Slit expression domains at locations where RGC axons make navigation errors in Hs2st-/- and Hs6st1-/- mutants and that Hs6st1-/- RGC axons are less sensitive to Slit2 repulsion than their wild-type counterparts in vitro. We suggest that (1) Hs2st and Hs6st1 are each deployed to generate distinct patterns of heparan sulfation on RGCs and at the optic chiasm and (2) this differential sulfation directs retinal axons through the chiasm, at least in part by modulating the response of the navigating growth cone to Slit proteins.

Why cavefish are blind.

Some fish exist as eyed, surface-dwelling and eyeless, cave-dwelling forms. The developmental processes that cause eye degeneration in different populations of Astyanax cavefish are similar. Although small optic primordia start to form, apoptosis of lens cells triggers developmental arrest and degeneration of the eyes. Degeneration has been linked to reduced expression of the transcription factor Pax6 in the anterior embryonic midline and optic primordia. Recently, Yamamoto and colleagues reported that increased expression of the diffusible morphogen Sonic hedgehog (Shh) at the embryonic midline of cavefish reduces pax6 expression and increases expression of Shh-regulated genes, which might confer selective advantages for life in caves.

The winged helix transcription factor Foxg1 facilitates retinal ganglion cell axon crossing of the ventral midline in the mouse.

During normal development, retinal ganglion cells (RGCs) project axons along the optic nerve to the optic chiasm on the ventral surface of the hypothalamus. In rodents, most RGC growth cones then cross the ventral midline to join the contralateral optic tract; those that do not cross join the ipsilateral optic tract. Contralaterally projecting RGCs are distributed across the retina whereas ipsilaterally projecting RGCs are concentrated in temporal retina. The transcription factor Foxg1 (also known as BF1) is expressed at several key locations along this pathway. Analysis of Foxg1 expression using lacZ reporter transgenes shows that Foxg1 is normally expressed in most, if not all, nasal RGCs but not in most temporal RGCs, neither at the time they project nor earlier in their lineage. Foxg1 is also expressed at the optic chiasm. Mice that lack Foxg1 die at birth and, although the shape of their eyes is abnormal, their retinas still project axons to the brain via the optic chiasm. Using anterograde and retrograde tract tracing, we show that there is an eightfold increase in the ipsilateral projection in Foxg1-/- embryos. The distributions of cells expressing the transcription factors Foxg1 and Nkx2.2, and cell-surface molecules Ephb2, ephrin B2 and SSEA-1 (Fut4) have been correlated to the normally developing retinothalamic projection and we show they are not much altered in the developing Foxg1-/- retina and optic chiasm. As much of the increased ipsilateral projection in Foxg1-/- embryos arises from temporal RGCs that are unlikely to have an autonomous requirement for Foxg1, we propose that the phenotype reflects at least in part a requirement for Foxg1 outwith the RGCs themselves, most likely at the optic chiasm.