Signaling - transcription interactions in mouse retinal ganglion cells early axon pathfinding -a literature review

Abstract

Sending an axon out of the eye and into the target brain nuclei is the defining feature of retinal ganglion cells (RGCs). The literature on RGC axon pathfinding is vast, but it focuses mostly on decision making events such as midline crossing at the optic chiasm or retinotopic mapping at the target nuclei. In comparison, the exit of RGC axons out of the eye is much less explored. The first checkpoint on the RGC axons' path is the optic cup - optic stalk junction (OC-OS). OC-OS development and the exit of the RGC pioneer axons out of the eye are coordinated spatially and temporally. By the time the optic nerve head domain is specified, the optic fissure margins are in contact and the fusion process is ongoing, the first RGCs are born in its proximity and send pioneer axons in the optic stalk. RGC differentiation continues in centrifugal waves. Later born RGC axons fasciculate with the more mature axons. Growth cones at the end of the axons respond to guidance cues to adopt a centripetal direction, maintain nerve fiber layer restriction and to leave the optic cup. Although there is extensive information on OC-OS development, we still have important unanswered questions regarding its contribution to the exit of the RGC axons out of the eye. We are still to distinguish the morphogens of the OC-OS from the axon guidance molecules which are expressed in the same place at the same time. The early RGC transcription programs responsible for axon emergence and pathfinding are also unknown. This review summarizes the molecular mechanisms for early RGC axon guidance by contextualizing mouse knock-out studies on OC-OS development with the recent transcriptomic studies on developing RGCs in an attempt to contribute to the understanding of human optic nerve developmental anomalies. The published data summarized here suggests that the developing optic nerve head provides a physical channel (the closing optic fissure) as well as molecular guidance cues for the pioneer RGC axons to exit the eye.

Keywords: development; optic nerve; optic stalk; retinal ganglion cells; transcription.

Figure 1

(A) Schematic illustration of eye morphogenesis. (B) Schematic developmental timeline of main events in mouse retinal ganglion cells development. grey arrow, developmental transformation; orange arrow, influence; RGC, retinal ganglion cells.

Figure 2

Schematic illustration of RGC axons pathfinding in the E12.5 mouse optic cup and stalk. Markers for each domain of the optic cup and stalk are listed in color code. (A) Lateral view. (B) Coronal section.

Figure 3

Schematic illustration of RGC axon guidance cues in the E12.5 mouse optic cup and stalk.