POU4F2 overexpression promotes the genesis of retinal ganglion cell-like projection neurons from late progenitors

ABSTRACT Retinal ganglion cells (RGCs) are the projection neurons of the retina, and their death promotes an irreversible blindness. Several factors were described to control their genesis during retinal development. These include Atoh7, a major orchestrator of the RGC program, and downstream targets of this transcription factor, including Pou4f factors, that in turn regulate key aspects of terminal differentiation. The absence of POU4F family genes results in defects in RGC differentiation, aberrant axonal elaboration and, ultimately, RGC death. This confirms the requirement of POU4F factors for RGC development and survival, with a crucial role in regulating RGC axon outgrowth and pathfinding. Here, we have investigated in vivo whether ectopic Pou4f2 expression in late retinal progenitor cells (late RPCs) is sufficient to induce the generation of cells with RGC properties, including long-range axon projections. We show that Pou4f2 overexpression generates RGC-like cells that share morphological and transcriptional features with RGCs that are normally generated during early development and extend axonal projections up to the brain. In conclusion, these results show that POU4F2 alone is sufficient to promote the crucial properties of projection neurons that arise from retinal progenitors outside their developmental window.