Contributions of VLDLR and LRP8 in the establishment of retinogeniculate projections

Abstract

BackgroundRetinal ganglion cells (RGCs), the output neurons of the retina, project to over 20 distinct brain nuclei, including the lateral geniculate nucleus (LGN), a thalamic region comprised of three functionally distinct subnuclei: the ventral LGN (vLGN), the dorsal LGN (dLGN) and the intergeniculate leaflet (IGL). We previously identified reelin, an extracellular glycoprotein, as a critical factor that directs class-specific targeting of these subnuclei. Reelin is known to bind to two receptors: very-low-density lipoprotein receptor (VLDLR) and low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2). Here we examined the roles of these canonical reelin receptors in retinogeniculate targeting.ResultsTo assess the roles of VLDLR and LRP8 in retinogeniculate targeting, we used intraocular injections of fluorescently conjugated cholera toxin B subunit (CTB) to label all RGC axons in vivo. Retinogeniculate projections in mutant mice lacking either VLDLR or LRP8 appeared similar to controls; however, deletion of both receptors resulted in dramatic defects in the pattern of retinal innervation in LGN. Surprisingly, defects in vldlr−/−;lrp8−/− double mutant mice were remarkably different than those observed in mice lacking reelin. First, we failed to observe retinal axons exiting the medial border of the vLGN and IGL to invade distant regions of non-retino-recipient thalamus. Second, an ectopic region of binocular innervation emerged in the dorsomedial pole of vldlr−/−;lrp8−/− mutant dLGN. Analysis of retinal projection development, retinal terminal sizes and LGN cytoarchitecture in vldlr−/−;lrp8−/− mutants, all suggest that a subset of retinal axons destined for the IGL are misrouted to the dorsomedial pole of dLGN in the absence of VLDLR and LRP8. Such mistargeting is likely the result of abnormal migration of IGL neurons into the dorsomedial pole of dLGN in vldlr−/−;lrp8−/− mutants.ConclusionsIn contrast to our expectations, the development of both the LGN and retinogeniculate projections appeared dramatically different in mutants lacking either reelin or both canonical reelin receptors. These results suggest that there are reelin-independent functions of VLDLR and LRP8 in LGN development, and VLDLR- and LRP8-independent functions of reelin in class-specific axonal targeting.

Nuclei-specific differences in nerve terminal distribution, morphology, and development in mouse visual thalamus

“…In these studies, the misrouting of retinal axons into non-retino-recipient regions of dorsal thalamus resulted in retinal terminals adopting nonretinal-like morphologies [64,65]. In fact, data from our own studies in mice lacking canonical Reelin receptors [48] support the notion that local environmental cues released by nuclei-specific cells pattern the targeting and differentiation of nerve terminals in mouse visual thalamus. At present, the nature of such cues remains unclear.…”

Physiologic Reelin does not play a strong role in protection against acute stroke

“…15,25 Vldlr, as one of the two canonical receptors for Reelin, is unlikely to be the main target of miR200-c in stroke, given our finding that loss of Reelin has no significant effect on tMCAo. However, there are Reelin-independent functions of Vldlr 26 that cannot be excluded. Conversely, Zeb1 enacts part of the protective response to ischemia by repressing transcription of a pro-apoptotic isoform of p73, 27 and thus its reduction by miR200-c may mediate the negative effect of miR200-c on post-stroke recovery.…”

Cell‐specific and developmental expression of lectican‐cleaving proteases in mouse hippocampus and neocortex

“…Fluorescent in situ hybridization (FISH) was performed on 16‐µm cryosectioned coronal sections as previously described (Su et al, ; Brooks et al, ). Sense and anti‐sense riboprobes were generated against Syt1 , Parv , Adamts4 , and Adamts15 .…”