Glial scaffold required for cerebellar granule cell migration is dependent on dystroglycan function as a receptor for basement membrane proteins
© Nguyen et al.; licensee BioMed Central Ltd. 2013
Received: 29 August 2013
Accepted: 2 September 2013
Published: 6 September 2013
Cobblestone lissencephaly is a severe neuronal migration disorder associated with congenital muscular dystrophies (CMD) such as Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type CMD. In these severe forms of dystroglycanopathy, the muscular dystrophy and other tissue pathology is caused by mutations in genes involved in O-linked glycosylation of alpha-dystroglycan. While cerebellar dysplasia is a common feature of dystroglycanopathy, its pathogenesis has not been thoroughly investigated.
Here we evaluate the role of dystroglycan during cerebellar development. Brain-selective deletion of dystroglycan does not affect overall cerebellar growth, yet causes malformations associated with glia limitans disruptions and granule cell heterotopia that recapitulate phenotypes found in dystroglycanopathy patients. Cerebellar pathology in these mice is not evident until birth even though dystroglycan is lost during the second week of embryogenesis. The severity and spatial distribution of glia limitans disruption, Bergmann glia disorganization, and heterotopia exacerbate during postnatal development. Astrogliosis becomes prominent at these same sites by the time cerebellar development is complete. Interestingly, there is spatial heterogeneity in the glia limitans and granule neuron migration defects that spares the tips of lobules IV-V and VI.
The full spectrum of developmental pathology is caused by loss of dystroglycan from Bergmann glia, as neither granule cell- nor Purkinje cell-specific deletion of dystroglycan results in similar pathology. These data illustrate the importance of dystroglycan function in radial/Bergmann glia, not neurons, for normal cerebellar histogenesis. The spatial heterogeneity of pathology suggests that the dependence on dystroglycan is not uniform.
Cerebellar histogenesis involves the formation and migration of several distinct populations of neural cells over an extended period of time, from late embryogenesis well into post-natal development . This intricate and protracted developmental process renders the cerebellum susceptible to a number of insults leading to a variety of cerebellar disorders. Cobblestone lissencephaly encompasses a spectrum of brain malformations, including cerebellar dysplasia, due to defects in neuronal migration. This brain malformation is found in a clinically severe subset of congenital muscular dystrophies (CMDs)—Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama CMD [2, 3]. Genetic, pathologic, and biochemical studies in patients and in mouse models support the hypothesis that the loss of alpha dystroglycan-ligand binding underlies the muscle, eye, and brain pathology present in these disorders [4–8].
Dystroglycan (DG), a central component of the dystrophin-glycoprotein complex, is known to contribute to basement membrane structure and stability through its function as a receptor for extracellular matrix (ECM) proteins [9, 10]. DG consists of an extracellular α-subunit linked to a transmembrane β-subunit. α-DG is decorated with a specific O-mannosyl glycan that functions as a high affinity receptor for ECM proteins such as laminin, agrin, and perlecan in a variety of tissues including brain [4, 11, 12], neurexin and Slit specifically in brain [13, 14], and pikachurin in retina . β-DG completes the link between the ECM and the intracellular actin cytoskeleton via its binding to α-DG outside the cell and dystrophin in the cytosol [16–19].
We previously reported that brain-selective deletion of DG in mice recapitulates some of the brain malformations characteristic of severe dystroglycanopathy, including aberrant migration of cortical and cerebellar neurons, and further showed severely blunted hippocampal long-term potentiation in these mice . Subsequent studies of mice with epiblast-specific deletion of DG resulted in brain and eye malformations that broadly resemble the clinical spectrum of the human disease, including neuronal migration errors, hydrocephalus, and defects in anterior as well as posterior chambers of the eye . Our most recent studies have shown DG is expressed in radial glia during neocortical histogenesis, and that glial DG is essential for multiple developmental processes, including maintenance of the basement membrane integrity, normal radial glia morphology, organization of neocortical proliferation, and cortical plate lamination . Moreover, there are distinct functions for glial and neuronal DG in the cerebrum—glial DG is critical for laminar development of the forebrain, while neuronal DG is necessary for proper hippocampal longterm potentiation .
In the developing cerebellum, DG mRNA is detected in all major cellular populations, including radial glia, granule cell (GC) precursors, and Purkinje cells (PC) , while its protein expression is prominent in Bergmann glia (BG) enfeet, perivascular astrocyte endfeet, and PCs in the adult cerebellum . How its expression in each of these cell types contributes to cerebellar development is not clearly understood. Here we show that DG in cerebellar GC and PC is largely dispensable for cerebellar histogenesis. In contrast, targeting both neurons and glia for DG deletion during embryonic development results in widespread, yet heterogeneous GC migration abnormalities without reducing overall cerebellar growth. Disruptions in the glia limitans and aberrant Bergmann glia (BG) organization coincide with GC migration errors and regions of gliosis, indicating that normal cerebellar histogenesis is dependent on proper BG scaffolds, which are achieved through extracellular interactions between glial α-DG and components of the ECM. These findings stress the importance of glial DG in its contribution to the basal lamina integrity during development and show that glial DG and neuronal DG have different biological functions in the cerebellum.
Generation of mice
Histology and immunofluorescence
For routine histology and histochemistry, postnatal mice were perfused with 4% PFA, then their brains removed and fixed for at least 24 hr by immersion in 4% PFA. Embryos and some postnatal mice were euthanized prior to fixation in Bouin’s solution. Brains were removed from older mice prior to immersion fixation, while the entire heads of embryos and younger postnatal mice were fixed in Bouin’s. Sagittal sections of the brains or heads were processed into paraffin blocks and sections cut at 6 μm. Serial sections were stained with hematoxylin and eosin and evaluated by routine light microscopy. Digital images were captured on a Zeiss microscope using standard proprietary software supplied by the manufacturers.
For immunofluorescence staining, brains were immersion fixed in 4% PFA, cryoprotected through increasing sucrose concentrations (10% to 20% to 30%) and embedded in OCT. For E14.5 embryos, the entire heads were fixed and processed for cryosections. Brains were removed from all postnatal mice prior to fixation. Alternatively, some brains were removed from postnatal mice and frozen without fixation in isopentane precooled with dry ice to approximately -75°C. Mid-sagittal sections of the cerebellum were cut on a cryostat at 10 μm, air-dried, and stored at -80°C prior to use. Stored sections were equilibrated in PBS at room temperature (RT) for 5 min and fixed for 10 min in 2% PFA. Sections were then incubated first in blocking solution (PBS containing 5% NGS, 0.1% Triton-X) for 1 hr, and then incubated with primary antibodies overnight at 4°C. Finally, sections underwent incubation with secondary antibodies for 1 hr at RT. Sections stained for BrdU were treated with 2 N HCl at 37°C for 30 min prior to blocking. All sections were counterstained with 0.01% DAPI or propidium iodide to label nuclei. Images were procured on a Zeiss ImageReady M1 fluorescence microscope. For quantification of data, ten images were obtained per section while three consecutive sections were acquired per animal, and three animals were considered per experimental group. Image adjustments and area measurements were done on Adobe Photoshop. Variabilities among data are expressed as mean ± SEM. Statistical analysis (one-way ANOVA with Tukey post-hoc test) was performed using SPSS software program and p < 0.05 was considered to be statistically significant.
Mouse pups between P0 and P16 were perfused through the heart left ventricle with 4% PFA prior to brain removal. A 0.1 cm midsagittal slice of the cerebellum was then immersion fixed in 2.5% glutaraldehyde and further processed as an intact slice through osmication, dehydration, and embedment in epon. Selected regions of the cerebellar slices were cut out of fully polymerized epon blocks with a jeweler’s saw and glued to blank epon stubs for sectioning and ultrastructural evaluation.
Mice received intraperitoneal injections of bromodeoxyuridine (BrdU, 50 mg/kg) 30 min prior to euthanasia to assess external granule cell proliferation or several days prior to euthanasia to assess granule cell migration.
The following primary antibodies are used: IIH6 (anti-αDG ), AP83 (anti-βDG ), anti-β1Itg , anti-AQP4 (Millipore AB3068), anti-BrdU (Abcam ab6326), anti-BLBP (Millipore AB9558), anti-calbindin (Millipore AB1778), anti-collagen IV (Abcam ab19808), anti-GABARA6 (Sigma G5544), anti-GFAP (Sigma G3893), anti-laminin (Sigma L9393), anti-Kir4.1 (Alomone Labs APC-035), anti-MAP2 (Sigma M4403), anti-NeuN (Millipore MAB377), anti-pax6 [Developmental Studies Hybridoma Bank (DSHB) PAX6] anti-perlecan (Millipore MAB1948), anti-shh (Abcam ab50515), anti-tag1 (DSHB 4D7), and anti-nestin (DSHB rat-401).
Secondary antibodies used in all experiments are Alexa Fluor fluorescent dye conjugates (Invitrogen): goat anti-mouse IgG1, goat anti-mouse IgM, goat anti-rabbit IgG, and goat anti-rat IgG.
Neuronal dystroglycan is not essential for cerebellar histogenesis
Dystroglycan is expressed in Purkinje cells (PCs) during early postnatal cerebellar development , and DG-positive puncta rimmed the PC somata and decorated PC dendrites across the molecular layer in the adult (P21) control cerebellum (Figure 2I). To assess whether loss of DG in PC is adequate to cause migration defects, we evaluated the histopathology of PCP2-Cre/DG-null mice. The PCP2 promoter drives Cre expression in PCs beginning on postnatal day 6 . The brains of these mice were grossly normal and many histologic sections were free of histopathology (Figure 2G, H). After thorough examination of several adult mice (n = 9), small, infrequent GC heterotopia were identified in the molecular layer of each cerebellum (Figure 2C, F), just internal to an intact glia limitans (Figure 2N). No disruptions of the glia limitans or abnormalities of Bergmann glia orientation were observed (Figure 2M, N) despite a nearly complete loss of PC dystroglycan (Figure 2L).
Granule cells in the cerebellar cortex express DG during their migration and lose expression during maturation in the internal granule cell layer, suggesting that expression of DG in GC may play a role during their migration . To determine whether the loss of DG in GC is sufficient to cause defects in GC migration, the histopathology of the cerebellum was examined in malpha6-Cre/DG-null mice, where DG is conditionally deleted from GCs. The malpha6 promoter drives Cre expression in GCs beginning at postnatal day 4 . The brains of these animals (n = 7) were grossly normal (Figure 2D) and GC ectopia were not observed (Figure 2E).
Cerebellar growth in conditional dystroglycan-null mice
Dystroglycan expression in the developing cerebellum
Disruptions at the glia limiting membrane correlate with radial glia/Bergmann glia irregularities
We further evaluated the expression of proteins known to associate with DG and the dystrophin-glycoprotein complex (DGC) in glial cells, namely aquaporin 4 (AQP4) and potassium inward rectifying channel 4.1 (Kir4.1). The membrane pore protein AQP4 comprising the major water channels in brain is clustered together with the DGC via interaction between AQP4 and α-syntrophin , which in turn binds to dystrophin and β-DG. In the cerebellum, AQP4 concentrated at the glia limitans in control (Additional file 5: Figure S5A, B) but was reduced at P8 and lost by P16 in the nestin-Cre/DG-null mice (Additional file 5: Figure S5D, E). Whether loss of AQP4 at glial endfeet in these mice causes other pathologic phenotypes remains to be investigated, but AQP4-null mice show no brain morphological defects, suggesting that the presence of ectopic cells in the nestin-Cre/DG-null mice is independent from AQP4. Kir4.1 is enriched at Müller glial endfeet abutting the inner limiting membrane in the retina; defects in Kir4.1 clustering and retinal physiology have been demonstrated in the nestin-Cre/DG-null mice . In the cerebellum, Kir4.1 is expressed in the molecular layer, but is not concentrated at the glia limitans. Expression of Kir4.1 was indistinguishable between nestin-Cre/DG-null and littermate control (Additional file 5: Figure S5C, F), indicating that Kir4.1 localization in the cerebellum, unlike in the retina, is not dependent on DG.
Proliferation and migration of postnatal granule cells
We additionally evaluated expression levels of sonic hedgehog (Shh)—a critical morphogen involved in the patterning of many brain structures during development—at P8 and P16 to confirm that GC proliferation and migration defects were independent from Shh pathways. Shh expression in the cerebellum was found to be comparable between nestin-Cre/DG-null and control littermates (Additional file 4: Figure S4).
Characterization of ectopic granule cells at sites of disrupted basal lamina
In addition to dystrophic skeletal muscle pathology, a spectrum of developmental brain abnormalities are associated with congenital muscular dystrophies caused by mutations in genes involved in the glycosylation pathways of dystroglycan [32, 33]. Cysts, hypoplasia, or dysplasia are among the prominent cerebellar pathologic features frequently observed in these dystroglycanopathy patients [2, 3]. Dystroglycan is expressed in important cell types of the cerebellum, including Bergmann glia, GCs, and PC [21, 22]. In this study, we show that glial DG, via interaction with the ECM at the glia limitans, is critical for normal cerebellar histogenesis, while neuronal DG is largely unnecessary.
The predominant phenotype observed in our conditional DG knockout models of cerebellar dysplasia is widespread GC migration errors, corroborated by BrdU pulse-chase labeling; a subset of GCs expressing markers of mature neurons remain on the EGL surface, at sites of disrupted glia limitans and aberrant glial organization as well as reactive gliosis. These phenotypes are remarkably similar to those described in previous cerebellar development studies of β1Itg-null mice . β1Itg is another laminin receptor that plays a role in GC precursor proliferation via its interaction with sonic hedgehog (Shh) and laminin. In the absence of β1Itg, GCs lose contact with the basement membrane, exit the cell cycle, and differentiate prematurely [26, 34]. Similar to β1Itg-null mice, our DG-null mice showed reduced GC proliferation at areas of highly disrupted glia limitans. However, further investigation showed relatively normal Shh expression in the absence of DG, and that Shh is even present in areas of ectopic GC (Additional file 4: Figure S4). Additionally, β1Itg itself is unable to compensate for the loss of DG, as its expression in Bergmann glia is not affected in the nestin-Cre/DG-null cerebellum (Figure 5H). Moreover, CNS deletion of integrin-linked kinase, an intracellular effector of β1Itg, results in abnormal cerebellar development associated with defects in glial process outgrowth, meningeal basement membrane assembly, and GC proliferation [35, 36]. In contrast, deletion of the cytoplasmic domain of β-DG did not result in disruptions of the glia limitans while displaying a mild cerebellar migration defect . This suggests that unlike β1Itg, whose intracellular signals are critical for cerebellar development, the extracellular interactions of α-DG are most crucial for cerebellar development.
In fact, the mucin domain of α-DG is decorated with LARGE-dependent phosphorylated O-mannosyl glycans that are responsible for α-DG high affinity binding activity [37, 38]. The Largemyd mice harbor a spontaneous mutation the Large gene, which results in hypoglycosylated α-DG and loss of ligand binding [4, 39]. These mice develop many of the brain malformations associated with severe forms of dystroglycanopathy, including disruption of the basement membrane and aberrant neuronal migration in the cerebrum and cerebellum [4, 40, 41]. A mouse model harboring the T192M mutation in DG shows impaired LARGE-mediated modification of phosphorylated O-mannosyl glycans on α-DG and reduced ligand-binding affinity . However, these mice show no gross structural abnormality in the brain, suggesting that the residual ligand-binding activity of α-DG is sufficient for normal brain laminar development. Taken together, the pathological resemblance between the Largemyd, nestin-Cre/DG-null, and GFAP-Cre/DG-null mice, and the lack of brain malformation in the T192M mice further support the hypothesis that extracellular interactions of α-DG in glia are critical for basal lamina integrity, a proper glial scaffold, and normal neuronal migration.
Although the distribution of GC ectopia was similar between GFAP-Cre/DG-null and nestin-Cre/DG-null mice, the severity of pathology was greater in nestin-Cre/DG-null cerebella. Since GFAP-Cre/DG-null mice retain expression of DG in PCs, it is possible that DG expression in PCs partially compensates for the loss of DG expression in other cell types or that PC DG has a function in GC migration. During their migration through the ML, GCs extend parallel fibers and make synaptic contacts with dendritic arbors of PC, and it has been suggested that adhesion molecules mediate the contacts between migrating neurons and PCs helping to direct migrating GCs into the IGL . DG may be one of the adhesion molecules that mediates these interactions. However, genetic experiments using PCP2-Cre/DG-null mice revealed only small GC heterotopia compared to nestin-Cre or GFAP-Cre mice, showing that PC DG has a very minor role in cerebellar histogenesis. Alternatively, the mild phenotype observed in the PCP2-Cre/DG-null mice could be attributed to the small amount of residual DG expressed in PCs or the relatively late loss of DG during cerebellar development. While the postnatal inward radial migration of GC begins soon after birth and continues until P16, the PCP2 transgene is not expressed until P6 and does not become robust until P16 . Similar experiments with malpha6-Cre/DG-null mice failed to discern a role for DG expression in GC. The malpha6 transgene is expressed in GC precursors during the peak of GC migration , yet no ectopic GC were observed in these mice.
Mapping the glia limitans and ectopic granule cell pathology in nestin-Cre and GFAP-Cre/DG null mice demonstrated a spatial heterogeneity along the glia limitans that has not previously been identified. Although our studies showed that perlecan, collagen IV, and laminin are all similarly perturbed at areas of disrupted basal lamina and all preserved at the surface of lobules IV-V and VI, we hypothesize that variation in spatial and temporal expression of extracellular matrix (ECM) proteins could explain the spatial heterogeneity of pathology observed in the nestin-Cre/DG null and GFAP-Cre/DG null mice. It is well established that expression of ECM components changes as basement membranes mature and likely involves the initial binding of laminin to dystroglycan with subsequent polymerization of further laminin chains and the cross-linking of the laminin superstructure with other ECM components . Alternatively, there may be spatial and temporal differences in the glial endfeet receptors for ECM proteins during development, even though no spatial heterogeneity in the expression of dystroglycan or β1-integrin was observed in our work. Rather than viewing basement membranes within a given tissue as homogenous structures changing uniformly over time, further exploration of their assembly and maintenance as spatially heterogeneous structures is warranted.
This work was supported in part by the Paul D. Wellstone Muscular Dystrophy Cooperative Research Center Grant (U54NS053672), R21-NS39734, and a Muscular Dystrophy Association Research Grant. K.P.C. is an Investigator of the Howard Hughes Medical Institute. We thank members of the Moore and Campbell laboratories for comments on this work and Joel Carl for his assistance with the figures.
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