Lama1 mutations lead to vitreoretinal blood vessel formation, persistence of fetal vasculature, and epiretinal membrane formation in mice
© Edwards et al; licensee BioMed Central Ltd. 2011
Received: 27 April 2011
Accepted: 14 October 2011
Published: 14 October 2011
Valuable insights into the complex process of retinal vascular development can be gained using models with abnormal retinal vasculature. Two such models are the recently described mouse lines with mutations in Lama1, an important component of the retinal internal limiting membrane (ILM). These mutants have a persistence of the fetal vasculature of vitreous (FVV) but lack a primary retinal vascular plexus. The present study provides a detailed analysis of astrocyte and vascular development in these Lama1 mutants.
Although astrocytes and blood vessels initially migrate into Lama1 mutant retinas, both traverse the peripapillary ILM into the vitreous by P3. Once in the vitreous, blood vessels anastomose with vessels of the vasa hyaloidea propria, part of the FVV, and eventually re-enter the retina where they dive to form the inner and outer retinal capillary networks. Astrocytes continue proliferating within the vitreous to form a dense mesh that resembles epiretinal membranes associated with persistent fetal vasculature and proliferative vitreoretinopathy.
Lama1 and a fully intact ILM are required for normal retinal vascular development. Mutations in Lama1 allow developing retinal vessels to enter the vitreous where they anastomose with vessels of the hyaloid system which persist and expand. Together, these vessels branch into the retina to form fairly normal inner retinal vascular capillary plexi. The Lama1 mutants described in this report are potential models for studying the human conditions persistent fetal vasculature and proliferative vitreoretinopathy.
The retinal vasculature, which nourishes the inner retina, consists of three plexi: the superficial in the nerve fiber layer, the intermediate in the inner plexiform layer, and the deep in the outer plexiform layer. The photoreceptors in the outer retina are maintained by the choroidal vessels. Retinal vessels develop in man during fetal development  but in mice during the first 3 post-natal weeks . Prior to the formation of retinal vessels, the lens and developing inner retina are nourished by the hyaloid vasculature. This three component vasculature (hyaloid artery, vasa hyaloidea propria, and tunica vasculosa lentis) lies in the vitreous, a gel-like structure separating the retina and the lens. The hyaloid vessels regress as retinal vessels form and are gone in humans by birth and by three weeks in the mouse. The portion of the hyaloid vasculature closest to the retina is the vasa hyaloidea propria (VHP) which is also the last to regress.
The proximity of the internal limiting membrane (ILM) to retinal astrocytes and the superficial vasculature suggests that this structure may be important for development of retinal blood vessels. Indeed, several mouse mutants with disruptions to the ILM have an abnormal retinal vasculature [11–14]. Laminin α1 is a primary component of laminin 111, which is believed to be important for basement membrane formation [15–18]. In addition, this laminin chain links the ILM to receptors, such as integrins and dystroglycan , which are found on Müller cells in the retina [20, 21]. Retinal vascular defects have recently been described in two mouse lines with mutations in Lama1, the gene which encodes laminin α1 . While the vascular defects are similar, the two mutants differ in their generation and effect on laminin α1, one being a recessive point mutation (Lama1 nmf223 ) and the other being a conditional knockout that leads to the complete loss of Lama1 (Lama1 tm1.Olf , herein referred to as Lama1 Δ ) but bypasses the embryonic lethality normally associated with laminin α1 deletion. In the Lama1 nmf223 mice, a chemically-induced mutation causes the replacement of a tyrosine with a cysteine at amino acid 265 (Y265C) in the N-terminal domain, which includes sites for receptors binding as well as polymerization . Here forward, Lama1 nmf223 and Lama1 Δ refer to mice homozygous for the respective mutations.
The present study investigates the development of retinal vessels in the previously described Lama1 mutants. Focus was placed on the Lama1 nmf223 because a random point mutation has greater potential to be associated with human disease than the complete deletion of Lama1, which is embryonic lethal in mice [15, 22] and likely to cause lethality in humans as well. The observation that a point mutation in this large gene causes retinal disease in mice suggests that it may also do so in humans. Transmission electron microscopy (TEM) was used for ultrastructural analysis of the ILM, glial cells, and blood vessels in these mice. Finally, epiretinal membranes are described in both of these mutants that have characteristics similar to human persistent fetal vasculature (PFV) and proliferative vitreoretinopathy (PVR).
Retinal vessels form in the Lama1nmf223retina at P1
Lama1nmf223retinal vessels migrate into the vitreous by P3
Only intravitreal vessels are evident in Lama1nmf223mice at P7
Intravitreal vessels invade the Lama1 nmf223 retina by P10
Adult Lama1 nmf223
Abnormal retinal vascular development in the Lama1 Δ mice is similar to that in Lama1 nmf223
The previous study reported that few, if any, retinal vessels developed in the Lama1 mutants and that these were replaced by persistent intravitreal vessels which penetrate the retina to form the intraretinal capillary networks . Using confocal microscopy, additional immunohistochemical markers, cross sectional analysis, and TEM, the present study redefines the development of retinal vessels and astrocytes in the Lama1 mutants. In addition, the previously described "vitreal fibroplasia" is identified as a vitreal membrane containing laminin-positive astrocytes, similar to human persistent fetal vasculature.
The ILM in the Lama1 nmf223 retina is normal in appearance throughout much of the retina but has small frequent breaks. By contrast, the Lama1 Δ mice have a very thin ILM with a diffuse, nonlinear appearance throughout much of the retina. In addition, breaks in the Lama1 Δ retina generally extended over larger areas of the retina. In many areas, the ILM was lacking completely. These findings are not surprising because an ILM lacking laminin α1 would likely not be bound well to the retina as this protein contains the binding sites for receptors on Müller cell endfeet [20, 21]. The preservation of the ILM in some areas suggests that other alpha chains present in the ILM, such as α5 , assist in binding this structure to the retina. Despite the differing ILM structure, the two Lama1 mutants have very similar abnormalities with regards to retinal vascular development.
Both mutants have a vascular apron around the optic nerve head at P1, suggesting that neither the Y265C mutation nor the complete loss of this protein affected endothelial cell differentiation and emigration from the optic nerve. Beginning around P3, however, it is evident that the retinal blood vessels cease to develop in the Lama1 nmf223 retina and have entered the vitreous where they remain until P7-P9. These vessels, which originate within the peripapillary retina grow along the retinal surface and eventually anastomose with those of the VHP. Together, these vessels form a dense vascular network in the vitreous that persists into adulthood and is ensheathed by astrocytes. These vitreal vessels sprout and invade the retina around P10 to form the retinal vascular capillary networks. Despite their abnormal origin, the Lama1 mutant retinal capillary networks at P10 (Figure 9E) are correctly placed within the retina. Therefore, the cues guiding these diving vessels are still present. It appears, however, as though the intermediate plexus forms early in the Lama1 nmf223 retina as vessels are evident in the inner plexiform layer at P10 compared to P14 in the WT retina.
The formation of the inner capillary networks further indicates that neither the Y265C point mutation in Lama1 nor the complete deletion of this protein alters the ability of endothelial cells to form blood vessels. Rather, astrocyte migration across the vitreal surface of the ILM precedes and likely causes the misguided migration of the blood vessels into the vitreous. In all retinas investigated at various ages, astrocytes were observed in the vitreous before retinal vessels traversed the ILM. In addition, only the VHP vessels were observed in the vitreous posterior to astrocytes on the vitreal aspect of the ILM. It is possible that if a normal template of astrocytes was present in the retina, the blood vessel development would also be normal. Therefore, identifying and neutralizing the factor(s) which stimulate astrocyte invasion into the vitreous may also alleviate the vascular defects in these mice. Most astrocytes from the Lama1 mutant retinas migrate towards and eventually envelop the VHP vessels. In addition, a subpopulation of these glial cells migrates from the optic nerve head directly into the vitreous along the hyaloid artery and its branches. These observations suggest that an attractant within the persistent and proliferating intravitreal vessels stimulates astrocyte migration. The previous report demonstrated that the tyrosine to cysteine mutation in the Lama1 nmf223 mice significantly decreases the binding ability of laminin α1 . It is logical to hypothesize, therefore, that this mutation disrupts the strength by which laminin α1 and, consequently, the entire ILM, bind to receptors on Müller cell endfeet. As a result, the ILM may become less of a barrier for cells in the retina. Astrocytes may, therefore, respond to chemoattractants in the vitreous more easily than those in the WT retina. Astrocyte migration into the vitreous in response to these chemoattractants may create breaks in the ILM. This idea is supported by the fact that in most cases, both laminin immunohistochemistry and TEM show the ILM pushed inwardly toward the vitreous where the cells exit the retina rather than there being a clear opening in the ILM through which cells migrate (Figure 7B, 13B). Indeed, a number of proteins within the normal vitreous are known to stimulate astrocyte migration, including hyaluronic acid , endothelin-1 , TGF-beta, and PDGF-AA . Among these, PDGF-AA is the best candidate as it is known to stimulate astrocyte migration and is believed to be generated by ganglion cells in the retina [8, 26]. Furthermore, PDGF-AA overexpression by the lens stimulates astrocyte migration into the vitreous, resulting in a pattern similar to that observed in the Lama1 mutants .
Once within the vitreous, most astrocytes migrate along the vitreal surface of the ILM towards the ora serrata. This migration pattern is similar to that seen within WT retinas with the exception that it occurs on the vitreal side of the ILM. This observation indicates that the migratory cues normally present inside the retina are on the vitreal surface of the ILM in Lama1 mutants. It could also be hypothesized that proteins constituting the ILM act as guidance cues and astrocytes in the mutant retina respond to these but remain on the vitreal side once they have traversed the ILM. Yet another theory is that Müller cells, the other retinal glial cell, guide astrocyte migration. Although Müller cells may not be fully differentiated, these glial cells are in place prior to astrocyte migration into and across the retina. Furthermore, Müller cell processes in both Lama1 mutants extend into the vitreous where chemoattractants they produce could spill out. In addition, some Müller cell endfeet are properly positioned, potentially contributing to frequent contact between vitreal astrocytes and the retina. Further investigation is required to identify the stimuli that guide astrocytes across the retina and, perhaps more importantly, what cell type(s) provide these stimuli.
The association of astrocytes with hyaloid vessels occurs in other rodent mutants with persistent fetal vasculature, including Collagen 15a1/18a1 double knockouts , LIF transgenics , and the Nuc1 rat . The question arises then, do astrocytes associate with vitreal vessels as a consequence of their failure to regress or is the astrocyte association preventing their regression by stabilizing the vasculature? In the case of the Lama1 mutants, the astrocytes migrate into the vitreous and associate with hyaloid and VHP by P3, before VHP regression has normally begun. This suggests that the astrocyte ensheathment of vitreal blood vessels subsequently inhibits the vessel regression and may even stimulate their proliferation.
Astrocyte ensheathment of the fetal vasculature in vitreous also occurs in the human disease PFV [29, 30]. PFV can be a blinding disorder because the retinal vasculature is incomplete and the persistent FVV and membrane pulls on the retina causing detachment . Preretinal glial membranes are often found in patients with PFV and likely contribute to retinal detachment [29, 31, 32]. It is not uncommon for patients with PFV to develop cataracts and glaucoma as well [31, 33]. Few animal models exist for this condition and treatment involves surgery. The Lama1 mutants described herein have two hallmark features of this disease: persistence of the fetal vasculature and preretinal glial membranes, making them potential models for studying this disease.
The membranes formed by astrocytes in Lama1 mutants also resemble epiretinal membranes seen in patients with proliferative vitreoretinopathy (PVR), a complication of retinal detachment in which retinal cells and macrophages enter the vitreous. The ultrastructure of the glial-containing membrane in Lama1 mutants is similar to that described for epiretinal membranes [34, 35]. In some areas, astrocytes extend thin, delicate processes across the vitreoretinal surface and into the vitreous. These created structures similar to those which Foos called glial bridges . In others areas, numerous astrocytes overlap one another to form a dense mesh-like structure. While the glial membranes in Lama1 mutants contain mainly tightly associated astrocytes, frequent irregularly large openings are also observed (Figure 13E). The astrocytes associated with this membrane make laminin, suggesting they may also produce other extracellular matrix proteins, a key feature in PVR. Current animals models for PVR are invasive, either injection of fibroblasts into vitreous or surgical disruption of the ILM to stimulate membrane formation .
The Lama1 mutants described herein provide novel, genetic models for studying PVR and PFV. The production and expression of laminin by vitreal astrocytes in Lama1 nmf223 mutants but not those in the retina indicates that they could contribute to the generation, expansion, and stabilization of the preretinal membranes. Astrocyte expression of laminin α1 and γ1 has been observed in association with glial activation during CNS disease [37, 38]. Furthermore, activated astrocytes express and secrete many cytokines which could alter the development of retinal vessels and promote membrane formation. A better understanding of how these vitreal membranes develop could help stop their formation or aid in treating them without surgery.
The present study describes a novel vascular phenotype in which vessels form initially the retina but then traverse the ILM and anastomose with hyaloid vessels. Interestingly, these vessels are able to re-enter the retina later in development and produce properly placed retinal capillary networks (Figure 1). The data presented in this report clearly demonstrates the importance of a fully functional ILM to retinal vascular development. The present study strongly suggests that mutations in LAMA1 or other ILM components in humans could cause retinal diseases such as PFV, PVR, and retinal detachment. Indeed, some Lama1 Δ mutants experience retinal detachments. Finally, the observation that astrocyte ensheathment of hyaloid vessels prior to their normal regression indicates that these glial cells may contribute to the persistence of these vessels. These models could increase understanding and aid in finding treatments for PFV and PVR.
Lama1 nmf223 mutants were bred and housed at the Johns Hopkins University and all experimental procedures were performed according to the Johns Hopkins University Animal Care and Use Committee standards. Homozygous matings were used to maintain this colony. C57BL/6J (B6) animals, the background strain of Lama1 nmf223 , were used as controls. Mice were maintained on a 12 hr light: dark cycle with food and water ad labium. Lama1 Δ mice were bred and housed under similar conditions at INSERM with approval of the INSERM animal care and use committee. Mice were genotyped as previously described . All procedures were in compliance with the ARVO statement for the use of animals for ophthalmological and vision research.
Fundus photography and fluorescein angiography
Fundus photographs of three adult Lama1 nmf223 and three control mice were taken using a Micron III indirect camera (Phoenix Research Labs). Mice were anesthetized using ketamine/Xylazine and eyes dilated with atropine. Fundus photographs were taken prior to the intraperitoneal injection of 50 μl sodium fluorescein (10%; Altaire Pharmaceuticals) while the retina was in focus on the Micron III. Images were taken as the retinal vasculature was filling with fluorescein and once all vessels were filled.
Mice were euthanized by an overdose of ketamine/Xylazine for all tissue collection. A minimum of three control and three mutant mice at each age group were used for all immunohistochemical studies. Images representative of all animals have been presented herein. For flatmount analysis, eyes were fixed for 1 hr in 2% paraformaldehyde (PFA) prior to retinal dissection and 1 hr post fixation in 2% PFA. After washing, retinas were blocked for 6 hrs at 4°C with 5% goat serum in Tris buffered saline containing 1% Triton X-100 (TBST) prior to incubation in primary antibody (diluted in 2% serum in TBST) for 18 hrs at 4°C. Following TBST washes, fluorescent conjugated secondary antibodies were applied (diluted 1:300 in 5% normal mouse serum in TBST; Jackson Immunoresearch) for 3 hrs. For blood vessel labeling, FITC conjugated GS isolectin (1:200; Invitrogen; 132450) was applied at the same time as the secondary immunohistochemistry antibody. For cryosections, eyes were cryopreserved as previously described . Eight micron sections were air dried and permeabilized with cold methanol prior to blocking in 2% goat serum in TBST containing 5% BSA. Sections were incubated in primary antibody for 2 hrs, washed, and incubated in secondary antibody along with 4', 6-diamidino-2-phenylindole (DAPI; 1:1000 Invitrogen, D21490) diluted in TBST for 30 min. Primary antibodies included: rabbit anti-GFAP (1:200; Dako; Z0334), rat anti-PDGFRα (1:500; CD140a; R&D, 558774), and rabbit anti-pan laminin (1:750; Sigma; L9393), which detects multiple laminin chains. Images were captured using a Zeiss 510 Meta confocal microscope in the Wilmer Imaging Core Facility.
TEM and JB-4
Eyes for TEM and JB-4 methacrylate (Polyscience) analysis were fixed in 2.5% PFA/2% glutaraldehyde in 0.1 M cacodylate buffer and processed as previously described [4, 39, 40]. Ultrastructural analysis was performed on at least two control and two mutant eyes at each age group described. At least two animals at each age from each group were embedded for JB-4. Additional animals were not analyzed because the abnormalities noted were consistent among the different ages invested as well as observations made using immunohistochemical techniques. TEM sections stained with uranyl acetate and JB-4 sections were stained with Periodic Acid-Schiffs reagent.
List of Abbreviations
fetal vasculature of vitreous
glial fibrillary acidic protein
- GS isolectin:
Griffonia simplicifolia isolectin B4
internal limiting membrane
persistent fetal vasculature
platelet-derived growth factor receptor alpha
post natal day
Tris buffered saline containing 1% Triton X-100
transmission electron microscopy
vasa hyaloidea propria
Acknowledgements and Funding
We would like to acknowledge support from the National Institute of Health [EY016551 (GAL) and Wilmer Core Grant (EY01765)], Research to Prevent Blindness (Unrestricted funds to Wilmer), and Ligue Contre Le Cancer, CCIR-GE (OL). We thank the Raab Family Foundation and the Wilmer Pooled Professor Fund for purchasing the Micron III Imaging System. We also wish to thank Annick Klein for technical assistance.
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