Pax2 regulates neuronal-glial cell fate choice in the embryonic optic nerve

During development, neural cell fate in the vertebrate optic nerve is restricted to the astroglial lineage. However, when isolated from the embryo and explanted in vitro, optic nerve progenitors generate neurons instead of astrocytes, suggesting that neuronal potentialities exist and are repressed in progenitors in vivo. Here we have investigated the mechanisms controlling cell fate in the optic nerve. The optic nerve is characterized by expression of the homeodomain transcription factor Pax2 which is maintained in differentiated astrocytes. We have observed that Pax2 is rapidly down-regulated in explanted optic nerves that generate neurons, and that its overexpression by electroporation in the optic nerve, or ectopically in the neural tube, is sufficient to block neuronal differentiation and allow glial development, showing that Pax2 plays a major role in controlling cell fate in the optic nerve. In vitro and ex vivo experiments further show that a signaling cascade that involves successively Sonic hedgehog and FGF is required to maintain Pax2 expression in optic nerve precursors whereby inhibiting the neuronal fate and promoting astroglial differentiation.