The LRR receptor Islr2 is required for retinal axon routing at the vertebrate optic chiasm

Abstract

BackgroundIn the visual system of most binocular vertebrates, the axons of retinal ganglion cells (RGCs) diverge at the diencephalic midline and extend to targets on both ipsi- and contralateral sides of the brain. While a molecular mechanism explaining ipsilateral guidance decisions has been characterized, less is known of how RGC axons cross the midline.ResultsHere, we took advantage of the zebrafish, in which all RGC axons project contralaterally at the optic chiasm, to characterize Islr2 as an RGC receptor required for complete retinal axon midline crossing. We used a systematic extracellular protein-protein interaction screening assay to identify two Vasorin paralogs, Vasna and Vasnb, as specific Islr2 ligands. Antibodies against Vasna and Vasnb reveal cellular populations surrounding the retinal axon pathway, suggesting the involvement of these proteins in guidance decisions made by axons of the optic nerve. Specifically, Vasnb marks the membranes of a cellular barricade located anteriorly to the optic chiasm, a structure termed the “glial knot” in higher vertebrates. Loss of function mutations in either vasorin paralog, individually or combined, however, do not exhibit an overt retinal axon projection phenotype, suggesting that additional midline factors, acting either independently or redundantly, compensate for their loss. Analysis of Islr2 knockout mice supports a scenario in which Islr2 controls the coherence of RGC axons through the ventral midline and optic tract.ConclusionsAlthough stereotypic guidance of RGC axons at the vertebrate optic chiasm is controlled by multiple, redundant mechanisms, and despite the differences in ventral diencephalic tissue architecture, we identify a novel role for the LRR receptor Islr2 in ensuring proper axon navigation at the optic chiasm of both zebrafish and mouse.

Molecular guidance cues in the development of visual pathway

“…Studies in the Zebrafish, in which all RGCs project contralaterally in the optic chiasm, show ipsilateral projections in the Isl2 mutant. These results also indicate an autonomous function of Islr2 during the axon path-finding (Panza et al, 2015 ). These results together demonstrate a specific role for Isl2 in inhibiting the ipsilateral projection.…”

“…These results together demonstrate a specific role for Isl2 in inhibiting the ipsilateral projection. Here Isl2 exhibits almost the same function in inhibiting the ipsilateral projections to the tectum and dLGN in mice and zebrafish, respectively (Thaler et al, 2004 ; Panza et al, 2015 ). Because the Isl2 null mutant pups died within 24 h after birth, the function of Isl2 during the eye-specific refinement is unknown.…”

Essential Role of Linx/Islr2 in the Development of the Forebrain Anterior Commissure

“…Further extended research into potential interacting proteins (ligands) with the members of the LIG protein family will be needed to fully elucidate their function. A biochemical screen to identify proteins that interact with the zebrafish orthologue of Linx/Islr2 has identified Vasorin as a candidate ligand for the Linx ECD 32 . Vasorin, also termed Slit-like 2 (SLITL2), is a known regulator of neural and vascular morphogenesis that is widely expressed among species 33 , 34 .…”

Construction and reconstruction of brain circuits: normal and pathological axon guidance

“…In addition, the transcription factor Islet2 is expressed by ~ 30% of cRGCs, mainly expressed by late‐born cRGCs (Pak et al ; Kuwajima et al ). Furthermore, the leucine‐rich repeat receptor Islr2 has been shown to be expressed on cRGCs and its deletion leads to aberrant ipsi‐lateral projections in Danio Rerio (Panza et al ).…”