Zic2 promotes axonal divergence at the optic chiasm midline by EphB1-dependent and -independent mechanisms

Axons of retinal ganglion cells (RGCs) make a divergent choice at the optic chiasm to cross or avoid the midline in order to project to ipsilateral and contralateral targets, thereby establishing the binocular visual pathway. The zinc-finger transcription factor Zic2 and a member of the Eph family of receptor tyrosine kinases, EphB1, are both essential for proper development of the ipsilateral projection at the mammalian optic chiasm midline. Here, we demonstrate in mouse by functional experiments in vivo that Zic2 is not only required but is also sufficient to change the trajectory of RGC axons from crossed to uncrossed. In addition, our results reveal that this transcription factor regulates the expression of EphB1 in RGCs and also suggest the existence of an additional EphB1-independent pathway controlled by Zic2 that contributes to retinal axon divergence at the midline.Research in the laboratory of E.H. is funded by grants from the Spanish Ministry of Education and Science (BFU2004-558, BFU2007-61831), CONSOLIDER-Ingenio 2010 Program (CDS2007-023), the Regional Government of ‘Generalitat Valenciana’, and a CDA from the Human Frontiers Science Program. Research in the laboratory of C.M. is funded by R01 EY12736 and EY01529 grants from the NIH.Peer Reviewe