Eye‐specific segregation and differential fasciculation of developing retinal ganglion cell axons in the mouse visual pathway

Abstract

Prior to forming and refining synaptic connections, axons of projection neurons navigate long distances to their targets. While much is known about guidance cues for axon navigation through intermediate choice points, whether and how axons are organized within tracts is less clear. Here we analyze the organization of retinal ganglion cell (RGC) axons in the developing mouse retinogeniculate pathway. RGC axons are organized by both eye-specificity and topography in the optic nerve and tract: ipsilateral RGC axons are segregated from contralateral axons and are offset laterally in the tract relative to contralateral axon topographic position. To identify potential cell-autonomous factors contributing to the segregation of ipsilateral and contralateral RGC axons in the visual pathway, we assessed their fasciculation behavior in a retinal explant assay. Ipsilateral RGC neurites self-fasciculate more than contralateral neurites in vitro and maintain this difference in the presence of extrinsic chiasm cues. To further probe the role of axon self-association in circuit formation in vivo, we examined RGC axon organization and fasciculation in an EphB1−/− mutant, in which a subset of ipsilateral RGC axons aberrantly crosses the midline but targets the ipsilateral zone in the dorsal lateral geniculate nucleus on the opposite side. Aberrantly crossing axons retain their association with ipsilateral axons in the contralateral tract, indicating that cohort-specific axon affinity is maintained independently of guidance signals present at the midline. Our results provide a comprehensive assessment of RGC axon organization in the retinogeniculate pathway and suggest that axon self-association contributes to pre-target axon organization.

Spatiotemporal distribution of glia in and around the developing mouse optic tract

“…We previously reported that ipsilateral RGCs are segregated by laterality within the optic tract (Sitko et al, ). Here, we confirmed the lateralization of ipsilateral RGCs in the optic tract by quantifying the distribution of zsGreen signal in the SERT‐Cre::zsGreen mouse across the mediolateral axis of the tract.…”

“…Pre‐target axon organization, a common feature of axon tracts (e.g., Imai et al, ; Zhou et al, ), is likely mediated by intrinsic axon–axon interactions, which are important for axon targeting (Wang et al, ), and extrinsic factors, including cues from surrounding cells, such as glia in and around the tract. RGC axons in the developing mouse retinogeniculate pathway are organized by both topography (Chan & Chung, ) and laterality (i.e., ipsi‐ and contralateral axons; Godement, Salaun, & Imbert, ), and ipsilateral RGC axons self‐fasciculate more than contralateral axons in vitro (Sitko, Kuwajima, & Mason, ). However, other mechanisms mediating pre‐target axon order in the developing optic tract, in particular, the tendency of ipsilateral RGC axons to course in the lateral tract, remain poorly understood.…”

Conversations with Ray Guillery on albinism: linking Siamese cat visual pathway connectivity to mouse retinal development

“…() after making lesions in the cat retina and silver staining to track degenerating axons. We gained more traction on the topic recently; with fluorescent dye‐ and genetic labeling we investigated eye‐specific organization of the mouse optic tract (Lee et al ., ; Sitko et al ., ).…”

“…After mingling with each other in the optic chiasm, crossed and uncrossed fibers immediately segregate in the proximal optic tract (Sitko et al ., ). The molecular underpinnings of this segregation are beginning to emerge, and include dystroglycan (Clements & Wright, ), matrix molecules (Reese et al ., , ; Hornberg et al ., ), glial cells (Reese et al ., ; Lee et al ., ), and elements important for local translation of guidance proteins (Hornberg et al ., ), but a strict expression pattern associated with the ipsi‐ vs. contralateral RGC populations has not been established.…”

“…The molecular underpinnings of this segregation are beginning to emerge, and include dystroglycan (Clements & Wright, ), matrix molecules (Reese et al ., , ; Hornberg et al ., ), glial cells (Reese et al ., ; Lee et al ., ), and elements important for local translation of guidance proteins (Hornberg et al ., ), but a strict expression pattern associated with the ipsi‐ vs. contralateral RGC populations has not been established. Our in vitro analyses indicate that mouse ipsilateral RGCs have a greater propensity to fasciculate with their own ‘kind’ compared with contralateral RGCs (Sitko et al ., ). Single cell genomic analyses should reveal candidates for such behavior leading to eye‐specific axon segregation in the optic tract.…”