Zic2 Patterns Binocular Vision by Specifying the Uncrossed Retinal Projection

Abstract

During CNS development, combinatorial expression of transcription factors controls neuronal subtype identity and subsequent axonal trajectory. Regulatory genes designating the routing of retinal ganglion cell (RGC) axons at the optic chiasm to the appropriate hemisphere, a pattern critical for proper binocular vision, have not been identified. Here, we show that the zinc finger transcription factor Zic2, a vertebrate homolog of the Drosophila gene odd-paired, is expressed in RGCs with an uncrossed trajectory during the period when this subpopulation grows from the ventrotemporal retina toward the optic chiasm. Loss- and gain-of-function analyses indicate that Zic2 is necessary and sufficient to regulate RGC axon repulsion by cues at the optic chiasm midline. Moreover, Zic2 expression reflects the extent of binocularity in different species, suggesting that Zic2 is an evolutionarily conserved determinant of RGCs that project ipsilaterally. These data provide evidence for transcriptional coding of axon pathfinding at the midline.

Axonal commissures in the central nervous system: how to cross the midline?

“…Similarly, inducing ectopic expression of EphB1 (but not of other Eph receptors such as EphB2) in commissural axons through targeted electroporation of the retina caused the axons to select an ipsilateral path [41]. Herrera and colleagues [42] have been interested by transcription factors from the Zic (zinc finger protein of the cerebellum) family. Zic factors (from 1 to 5) are involved in the specification of the body medial axis and in early Consequently, they are insensitive to EphrinB2's repulsive effect and are allowed to cross the midline.…”

Normal eye-specific patterning of retinal inputs to murine subcortical visual nuclei in the absence of brain-derived neurotrophic factor

“…Moreover, an overt emphasis on activitydependent mechanisms has overshadowed evidence for activityindependent mechanisms of eye-specific patterning. In particular, both axon guidance cues present at the optic chiasm (Erskine et al, 2000;Herrera et al, 2003;Williams et al, 2003) and targeting molecules present on retinal axons and in the LGd can significantly influence eye-specific patterning (Feldheim et al, 1998;Ellsworth et al, 2005). In the present study, we show that some retinal targets zones either show virtually complete integration of eye-specific projections, as in the suprachiasmatic nucleus, or virtually completely unilateral projections, such as the medial E-F: Confocal images of the rostral SC from sections processed for imaging 2 days after injection of fluorescent CTB conjugates (red channel, right eye's projection; green channel, left eye's projection).…”

“…Developmental labels for left eye versus right eye are unknown. Yet because the ipsilateral projection arises from the ventrotemporal region of retina (Sretavan, 1990;Sretavan & Kruger, 1998), a retinal region that selectively expresses a variety of markers (Feldheim et al, 1998;Pak et al, 2002;Herrera et al, 2003;Ellsworth et al, 2005), specific targeting of the ipsilateral and contralateral projections may be largely determined by molecular cues related to retinal position. Retinal activity may provide some permissive modulation (Cook et al, 1999;Huberman et al, 2003) of some aspects of this patterning.…”

Selective inhibition of ventral temporal but not dorsal nasal neurites from mouse retinal explants during contact with chondroitin sulphate

“…Furthermore, the response of neurites to this critical concentration of CS is dependent upon their location in the retina. A recent study has demonstrated that the uncrossed axons arise from ganglion cells that express the zinc finger transcription factor Zic2 (Herrera et al 2003). It would thus be of interest to investigate whether this transcription factor regulates the signalling mechanism that underlies the response of ganglion cell axons from the VT retina to CS at the midline of the chiasm.…”