Contributions of VLDLR and LRP8 in the establishment of retinogeniculate projections
© Su et al.; licensee BioMed Central Ltd. 2013
Received: 24 February 2013
Accepted: 22 May 2013
Published: 13 June 2013
Retinal 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.
To 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.
In 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.
KeywordsReelin Synaptic targeting Intergeniculate nucleus Retinogeniculate Lateral geniculate nucleus Axon Retinal terminal
Neural circuits associated with retinal ganglion cells (RGCs) have long been used as models for investigating the mechanisms that underlie circuit development and function. As the sole output neurons of the retina, RGCs must convey information regarding color, contrast, light intensity and object movement to specific regions within retino-recipient nuclei of the brain. For this reason, RGC axons project to over 20 distinct central nervous system (CNS) nuclei and are targeted to these sites by at least three distinct mechanisms. First, retinal axons are sorted topographically, so that the location of information in the visual field is accurately conveyed to a spatially correlated region of a retino-recipient nucleus. Ephs/ephrins, morphogens and transmembrane cell adhesion molecules all contribute to topographic targeting of retinal axons in the mammalian brain[1–3]. In addition to being topographically mapped, retinal axons are sorted into discrete domains of most retino-recipient nuclei based upon their eye of origin. The formation of eye-specific domains requires both axonal targeting cues (such as Eph/ephrins and teneurins)[4–6], and subsequent activity-dependent refining signals (such as MHC1, C1q and neuronal pentraxins)[7–10]. The third targeting mechanism involves axons from different functional classes of RGCs targeting distinct retino-recipient nuclei or different lamina (or domains) with these nuclei. Although axonal projection patterns have recently been described for several classes of RGCs[11–19], few studies have shed light on the mechanisms underlying such class-specific targeting. We recently identified reelin as a critical regulator of class-specific retinogeniculate targeting.
Reelin is a bulky, extracellular glycoprotein composed of an N-terminal f-spondin domain, eight repeated unique domains containing epidermal growth factor (EGF)-like motifs and a C-terminal domain rich in positively charged amino acids[21, 22]. A multitude of studies have shown roles for reelin in neuronal migration, axonal polarization, dendritic arborization and spine formation, growth cone guidance, axonal targeting, and synaptic function and plasticity[21–30]. We previously identified reelin in a screen for synaptic targeting cues that were differentially expressed in subnuclei of the lateral geniculate nucleus (LGN): the ventral LGN (vLGN), the dorsal LGN (dLGN) and the intergeniculate leaflet (IGL). Reelin is significantly enriched in vLGN and IGL during retinogeniculate circuit formation, and mice lacking reelin (reln rl/rl ) exhibit severe defects in retinal targeting of these regions. Targeting defects in reln rl/rl mutants result from the mistargeting of intrinsically photosensitive RGC (ipRGC) axons, whereas axons from other classes of RGCs appear unaffected by the absence of reelin.
Most functions of reelin have been attributed to its ability to bind two members of the low- density lipoprotein (LDL) receptor gene family: very-low-density lipoprotein receptor (VLDLR) and low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2)[32, 33]. Upon binding reelin, VLDLR and LRP8 activate the intracellular adaptor molecule disabled-1 (DAB1). Genetic deletion of both VLDLR and LRP8 or DAB1 result in mutant mice that outwardly resemble reln rl/rl mutants[32, 34–36]. Our previous studies on visual system development partially confirmed a similar molecular signaling pathway underlies reelin's function in retinal targeting: mice harboring a spontaneous mutation in DAB1 exhibit similar defects in retinogeniculate targeting as reln rl/rl mutants. In the present study we sought to expand these findings and test the roles of VLDLR and LRP8 in retinogeniculate targeting. We hypothesized that deletion of both canonical reelin receptors would produce defects in retinal targeting that closely resembled those in the absence of reelin. To our surprise, however, defects observed in mice lacking both VLDLR and LRP8 (vldlr −/− ;lrp8 −/− ) were strikingly different than those in reeler mutants. Results presented here suggest that there are both reelin-independent functions of VLDLR and LRP8, and VLDLR- and LRP8-independent functions of reelin in visual system development.
Deletion of both VLDLR and LRP8 disrupts retinogeniculate targeting
Retinogeniculate projection in phenotypes in wild-type and mutant mice
Smaller retino-recipient region of vLGN
Sparse retinal projections to IGL
Misrouted retinal axons exiting medial border of LGN
Ectopic retinal projections in dLGN
vldlr +/− ;lrp8 +/−
vldlr +/− ;lrp8 −/−
vldlr −/− ;lrp8 +/−
vldlr −/− ;lrp8 −/−
In the process of generating vldlr −/− ;lrp8 −/− mutants, a large number of single reelin receptor gene mutants were generated that carried only one copy of the other canonical reelin receptor (vldlr−/−;lrp8+/− and vldlr+/−;lrp8−/− mice). We analyzed retinal projections in these mice to test the affect of gene dosage of these receptors on retinal targeting. All of the defective phenotypes described above for double mutants were observed in mutant heterozygote mice, although phenotypes were typically not as dramatic and not as penetrant as in double mutants (Table 1).
Deletion of both VLDLR and LRP8 misroutes retinal axons to the dorsomedial pole of dLGN
Cytoarchitectural defects in the LGN of vldlr −/− ;lrp8 −/− mutants
To further confirm cytoarchitectural differences in the dorsomedial pole of vldlr −/− ;lrp8 −/− mutant dLGN, we next assessed the presence of other types of nerve terminals present in dLGN. A large portion of inputs to dLGN arise from corticothalamic (CT) axons originating from layer VI of visual cortex. Terminals from these CT axons contain the synaptic vesicle associated protein, vesicular glutamate transporter 1 (VGluT1)[37, 41]. While dense populations of VGluT1-containing terminals were present throughout the dorsal thalamus and dLGN of vldlr −/− ;lrp8 −/− mutants, they appeared absent from the dorsomedial pole of mutant dLGN (Figure 6F). Taken together, studies on the distribution of adamts15 mRNA, SMI32-IR and VGluT1-containing terminals all suggest that the dorsomedial pole of vldlr −/− ;lrp8 −/− mutant dLGN is cytoarchitecturally different than adjacent regions of dLGN.
The final similarity in abnormal retinal projections in vldlr −/− ;lrp8 −/− and reln rl/rl mutants is an incomplete refinement of retinal terminals into eye-specific domains (Figure 9), an essential feature in the establishment of visual system circuits[1, 42]. Impaired refinement of retinal projections was also observed in dab1 scm/scm , vldlr−/−, and lrp8−/− mutants (Figure 1C,D and data not shown). Since refinement of eye-specific arbors requires retinal activity, defects in eye-specific segregation is not entirely unexpected in these mutants. Retinal activity has previously been shown to be perturbed in the absence of reelin, DAB1, VLDLR or LRP8[43, 44].
Despite the above described similarities in retinal projections in vldlr −/− ;lrp8 −/− and reln rl/rl mutants, two more notable differences in phenotypes were observed in our studies. First, the deletion of both canonical reelin receptors largely failed to generate bundles of misrouted retinal axons that exited the medial borders of the vLGN and IGL, and invaded non-retino-recipient regions of thalamus. Misrouting of axons from ipRGCs into medial thalamus was a distinguishing feature of retinal targeting in the absence of either reelin or DAB1[20, 31]. The lack of ipRGC axons erroneously exiting the medial border of IGL in vldlr −/− ;lrp8 −/− mutants may help explain why projections to the IGL in these double mutants appears more developed than in reln rl/rl mutants. Second, an ectopic region of binocular retinal input was observed in the dorsomedial pole of vldlr −/− ;lrp8 −/− LGN (Figure 9), a feature never observed in mutants lacking reelin or functional DAB1. Cytoarchitectural analyses demonstrated that NPY-expressing IGL neurons aberrantly migrate into this region of vldlr −/− ;lrp8 −/− dLGN, and despite being displaced these cells generate a micro-domain that is uniquely distinct from surrounding dLGN and dorsal thalamus. Based on the density of NeuN-positive neurons in this micro-domain we suspect that additional types of non-NPY expressing classes of IGL neurons may also be present in this ectopic region. Certainly, reelin-expressing cells, which normally populate both IGL and vLGN, were present in this micro-domain of mutant dLGN. In wild-type tissue, a cohort of glial fibrillary acidic protein (GFAP)-expressing astrocytes also populate IGL but not the surrounding tissue. Surprisingly, we failed to observe GFAP-immunoreactivity in the dorsomedial pole of vldlr −/− ;lrp8 −/− mutant dLGN, suggesting that these cell populations were less affected by the loss of VLDLR and LRP8 (data not shown), and hinting that these glial cells are not the source of reelin in the IGL. Based on the presence of IGL target neurons and reelin in the dorsomedial pole of mutant dLGN, we posit that IGL-projecting classes of retinal axons are misrouted into this micro-domain of mutant dLGN. In support of this hypothesis, retinal arbors in this micro-domain remain unsegregated based on their eye of origin and form small terminals, two features that are hallmarks of retinal projections in wild-type IGL. Taken together, data presented here paint a picture that VLDLR and LRP8 have reelin-independent roles in the migration of IGL neurons during thalamic development. Likewise, the lack of misrouted ipRGC axons into medial thalamus suggests that reelin signals through other receptors for the establishment of class-specific retinogeniculate circuits.
What might these non-canonical reelin receptors be? Despite the plethora of studies on reelin’s function in neural development and synaptic function few receptors other than VLDLR and LRP8 have been identified. Integrin α3β1 binds to the N-terminal f-spondin domain of reelin and can activate DAB1 in a reelin-dependent manner[46, 47]. Since disruption in α3β1 signaling does not result in severe defects in neuronal position (like deletion of reelin or DAB1), it has been suggested that reelin-α3β1 integrin interactions may be more essential during neurite outgrowth, synapse formation or synaptic function[47–49]. Based on its established role in neurite extension[50, 51] and expression in retinal axons, α3β1 integrin is a prime candidate to mediate the class-specific axon targeting function of reelin in mouse LGN. However, another prime candidate for mediating reelin’s role in axon targeting in the visual system is amyloid precursor protein (APP), a transmembrane receptor with established roles in mediating neurite outgrowth[53, 54] and synapse assembly. APP binds to the central repeating domain of reelin (reelin repeats 3 to 6), an interaction that promotes neurite outgrowth. These findings, together with the fact that APP is expressed by at least some mammalian RGCs, make APP a reasonable candidate for mediating the class-specific axon targeting function of reelin in LGN. The last non-canonical reelin receptor that we shall discuss is the protocadherin cadherin-related neuronal receptor 1 (CNR1). CNR1 remains a controversial reelin binding partner[59, 60], but due to isoform diversity and alternative splicing the cadherin superfamily (which includes classical cadherins, protocadherins, FAT-family cadherins, T-cadherins and 7TM-cadherins) has been of particular interest for its role in the specific wiring of neural circuits[61, 62]. Based upon the expression of many cadherins and protocadherins by RGCs, and the role of classical cadherins in RGC axon targeting[63–66], CNR1 is an intriguing candidate receptor for mediating the class-specific axon targeting function of reelin in LGN.
Finally, what non-reelin ligand might bind and activate VLDLR and LRP8 to affect neuronal migration during thalamic development? Since both VLDLR and LRP8 are members of the LDL family of lipoprotein receptors they can bind a variety of lipoproteins including compounds containing apolipoprotein E (ApoE). ApoE has been shown to affect cell migration in a variety of systems, suggesting it may be the LGN ligand for VLDLR and LRP8. However, other candidate extracellular ligands with known roles in cell migration have also been identified. Both canonical reelin receptors are also capable of binding thrombospondin (THBS), a bulky extracellular proteoglycan present in the developing brain[68, 69]. Like reelin, binding of THBS to VLDLR and LRP8 activates DAB1, but the subsequent downstream signaling events differ from that of reelin induced signals. Our previous studies identified an isoform of THBS, THBS4, as being one of the extracellular cues most significantly enriched in vLGN/IGL compared with dLGN at perinatal ages of mouse development. Roles for thrombospondins in LGN development remain unresolved.
Identifying the molecular underpinnings of class-specific targeting of axons to correct brain regions is essential for our understanding of how complex neural circuits are assembled. Visual system circuits are ideal models to study class-specific axonal targeting since there are over 20 distinct classes of RGCs in the mammalian retina, each with a unique stereotyped pattern of axonal projections to a cohort of retino-recipient nuclei within the brain[11–19, 70–73]. Such diversity of neuronal subtypes and class-specific circuitry is not unique to the retina, but instead is a central feature of many regions of the mammalian brain. In a previous study we identified reelin, a bulky extracellular proteoglycan, as a critical molecular component required for the targeting of LGN subnuclei by distinct classes of retinal axons. Here we addressed whether this function of reelin required the two canonical reelin receptors, VLDLR and LRP8. While genetic deletion of either VLDLR or LRP8 had little affect on the initial targeting of retinal axons to LGN subnuclei (despite clear affects on the refinement of these axons into segregated, eye-specific domains), several defects were observed in retinal axon targeting in mutant mice lacking both receptors. However, in contrast to our hypothesis that reelin would utilize these receptors for class-specific retinogeniculate targeting, we found that deletion of both canonical reelin receptors failed to accurately phenocopy retinal targeting defects present in reln rl/rl mutant LGN. The misrouting of retinal axons into medial, non-retino-recipient thalamus in the absence of reelin were not observed in vldlr −/− ;lrp8 −/− mutants and aberrant patterns of retinal projections seen in vldlr −/− ;lrp8 −/− mutants (which appeared secondary to defects in neuronal migration) were not observed in mutants lacking reelin. We take these results to suggest that non-canonical reelin receptors contribute to reelin’s role in retinogeniculate targeting, and other extracellular ligands activate VLDLR and LRP8 for the proper migration of IGL neurons.
Wild-type C57 mice were obtained from Charles River (Wilmington, MA, USA). Reeler mutant mice (relnrl/rl), vldlr −/− and lrp8 −/− mice were obtained from The Jackson Laboratory (Bar Harbor, ME, USA). Genomic DNA was isolated from tail and genotyping performed as previously described[31, 74–76]. The following primer pairs were used: reln, TTA ATC TGT CCT CAC TCT GCC CTC T and GCA GAC TCT CTT ATT GTC TCT AC; mutant reln, TTA ATC TGT CCT CAC TCT GCC CTC T and TTC CTC TCT TGC ATC CTG TTT TG; vldlr, TGG TGA TGA GAG GCT TGT ATG TTG TC and TTG ACC TCA TCG CTG CCG TCC TTG; mutant vldlr, CGG CGA GGA TCT CGT CGT GAC CCA and GCG ATA CCG TAA AGC ACG AGG AAG; lrp8, CCA CAG TGT CAC ACA GGT AAT GTG and ACG ATG ACC CCA ATG ACA GCA GCG; mutant lrp8, GAT TGG GAA GAC AAT AGC AGG CAT GC and GCT TGT TGG AAT TCA GCC AGT TAC C. All analyses conformed to National Institutes of Health (NIH) guidelines and protocols, approved by the Virginia Polytechnic Institute and State University, and Virginia Commonwealth University (VCU) Institutional Animal Care and Use Committees.
Antibodies for the following antigens were purchased: rabbit anti-VGluT2 and rabbit anti- VGluT1 (diluted 1:500; Synaptic Systems, Göttingen, Germany), mouse anti-reelin (diluted 1:1000; Abcam, Cambridge, UK), rabbit anti-NPY (diluted 1:500; ImmunoStar, Hudson, WI, USA), mouse anti-NeuN (diluted 1:200; Millipore, Billerica, MA, USA), rabbit anti-glutamate decarboxylase 65/67 (GAD65/67) (diluted 1:500; Millipore Bioscience Research Reagents, Temecula, CA, USA), and mouse anti-SMI32 (diluted 1:500; Covance, Princeton, NJ, USA). Fluorescently conjugated secondary antibodies were purchased from Invitrogen (Carlsbad, CA, USA) or Jackson ImmunoResearch (diluted 1:1000; West Grove, PA, USA).
Immunohistochemistry (IHC) was performed on 16 μm coronal cryosectioned tissues as previously described[31, 38, 74, 76]. Briefly, tissue slides were allowed to air dry for 15 minutes before being incubated with blocking buffer (2.5% normal goat serum, 2.5% bovine serum albumin and 0.1% Triton X-100 in PBS) for 30 minutes. Primary antibodies were diluted in blocking buffer and incubated on tissue sections for overnight at 4°C. On the following day, tissue slides were washed in PBS and secondary antibodies diluted 1:1000 in blocking buffer were applied to slides for 1 hour at room temperature. After thoroughly washing in PBS, tissue slides were coverslipped with VectaShield (Vector Laboratories, Burlingame, CA, USA). Images were acquired on a Zeiss Axio Imager A2 fluorescent microscope, a Zeiss Examiner Z1 LSM 710 confocal microscope, or a Zeiss LSM 700 confocal microscope (Oberkochen, Germany). When comparing different ages of tissues or between genotypes, images were acquired with identical parameters. The size of VGluT2-immunoreactive retinal terminals was measured with ImageJ (NIH, Bethesda, MD, USA). The area of individual puncta in control and mutant vLGN, IGL and dLGN were measured manually. A minimum of three animals (per genotype and per age) was compared in all IHC experiments.
In situ hybridization
In situ hybridization (ISH) was performed on 16 μm coronal cryosectioned tissues as previously described[31, 74, 76]. The generation of adamts15 (clone IDs 30619053) riboprobes was previously described. Briefly, riboprobes were synthesized using digoxigenin (DIG)-labeled UTP (Roche, Mannheim, Germany) and the MAXIscript In Vitro Transcription Kit (Ambion, Austin, TX, USA). Probes were hydrolyzed to 500 nt. Coronal brain sections were prepared and hybridized at 65°C as previously described (Su et al., 2010), and bound riboprobes were detected by horseradish peroxidase (POD)-conjugated anti-DIG antibodies and fluorescent staining with Tyramide Signal Amplification (TSA) systems (PerkinElmer, Shelton, CT, USA). Images were obtained on a Zeiss Axio Imager A2 fluorescent microscope or a Zeiss Examiner Z1 LSM 710 confocal microscope. A minimum of three animals per genotype and age was compared in ISH experiments.
Intraocular injections of anterograde tracers
Intraocular injection of CTB conjugated to Alexa Fluor 488 or Alexa Fluor 594 (Invitrogen) was performed as previously described[31, 39]. Briefly, mice were anesthetized with hypothermia (<P7) or by isoflurane vapors (>P7). The sclera was pierced with a sharp-tipped glass pipette and excess vitreous was drained. Another pipette, filled with a 0.1 to 0.2% solution of CTB, was inserted into the hole made by the first pipette. The pipette containing the CTB was attached to a picospritzer and a prescribed volume (1 to 3 μl at P3 to P10 and 3 to 5 μl for ages >P10) of solution was injected into the eye. After 1 to 2 days, mice were killed and brains were fixed in 4% paraformaldehyde. A total of 100 μm coronal sections were sectioned on a vibratome (Microm HM 650 V; Thermo Scientific, Waltham, MA, USA) and mounted in ProLong Gold (Invitrogen). Retinal projections were analyzed from between 3 to 12 animals for each age and genotype. Images were acquired on a Zeiss Examiner Z1 LSM 710 confocal microscope or a Zeiss LSM 700 confocal microscope. We documented four types of defects in retinogeniculate targeting in wild-type (control), reln rl/rl , vldlr −/− , lrp8 −/− , vldlr −/− ;lrp8 −/− , vldlr −/− ;lrp8 +/− and vldlr +/− ;lrp8 −/− mice: 1) smaller pattern of retinal projection to vLGN; 2) an absence of retinal axons between vLGN and IGL; 3) retinal axons abnormally exiting the medial border of the vLGN with IGL; and 4) retinal axons from both ipsilateral and contralateral retinas that ectopically innervate to the dorsomedial pole of dLGN. We scored these phenotypes objectively based on penetrance and subjectively based on robustness. All sections were scored blind by at least two observers.
A disintegrin and metalloproteinase with thrombospondin type 1 motif member 15
Analysis of variance
Apolipoprotein E receptor 2
Amyloid precursor protein
Cadherin-related neuronal receptor 1
Central nervous system
Cholera toxin B subunit
Dorsomedial pole of dLGN
Epidermal growth factor
Glial fibrillary acidic protein
Intrinsically photosensitive RGC
In situ hybridization
Lateral geniculate nucleus
Low-density lipoprotein receptor-related protein 8
National Institutes of Health
Retinal ganglion cell
Tyramide Signal Amplification
Virginia Commonwealth University
Vesicular glutamate transporter 1
Vesicular glutamate transporter 2
Very-low-density lipoprotein receptor
This work was supported by the NIH (EY021222) (MAF), the Thomas F Jeffress and Kate Miller Jeffress Memorial Trust (MAF), and the VCU Presidential Research Incentive Program (PRIP) (MAF). A small portion of the microscopy was performed at the VCU Microscopy Core supported, in part, with funding from NIH (NS047463).
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