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Loss of Col3a1, the Gene for Ehlers-Danlos Syndrome Type IV, Results in Neocortical Dyslamination

  • Sung-Jin Jeong,

    Affiliation Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

  • Shihong Li,

    Affiliation Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

  • Rong Luo,

    Affiliation Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

  • Natalie Strokes,

    Affiliation Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

  • Xianhua Piao

    xianhua.piao@childrens.harvard.edu

    Affiliation Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

Loss of Col3a1, the Gene for Ehlers-Danlos Syndrome Type IV, Results in Neocortical Dyslamination

  • Sung-Jin Jeong, 
  • Shihong Li, 
  • Rong Luo, 
  • Natalie Strokes, 
  • Xianhua Piao
PLOS
x

Abstract

It has recently been discovered that Collagen III, the encoded protein of the type IV Ehlers-Danlos Syndrome (EDS) gene, is one of the major constituents of the pial basement membrane (BM) and serves as the ligand for GPR56. Mutations in GPR56 cause a severe human brain malformation called bilateral frontoparietal polymicrogyria, in which neurons transmigrate through the BM causing severe mental retardation and frequent seizures. To further characterize the brain phenotype of Col3a1 knockout mice, we performed a detailed histological analysis. We observed a cobblestone-like cortical malformation, with BM breakdown and marginal zone heterotopias in Col3a1−/− mouse brains. Surprisingly, the pial BM appeared intact at early stages of development but starting as early as embryonic day (E) 11.5, prominent BM defects were observed and accompanied by neuronal overmigration. Although collagen III is expressed in meningeal fibroblasts (MFs), Col3a1−/− MFs present no obvious defects. Furthermore, the expression and posttranslational modification of α-dystroglycan was undisturbed in Col3a1−/− mice. Based on the previous finding that mutations in COL3A1 cause type IV EDS, our study indicates a possible common pathological pathway linking connective tissue diseases and brain malformations.

Introduction

Cortical dyslamination is an important cause of neurological morbidity. Cobblestone lissencephaly is one common form of cortical dyslamination, in which neurons migrate beyond the breached pial BM and form ectopias on the surface of the brain [1]. Cobblestone lissencephaly is seen in three types of human congenital muscular dystrophy syndromes; Walker -Warburg syndrome (WWS), Fukuyama-type muscular dystrophy (FCMD), and muscle-eye-brain disease (MEB). WWS is the most severe form of congenital muscular dystrophy, with the vast majority of patients dying in utero or in early infancy. The genetic cause for MEB, FCMD, and some WWS cases is aberrant glycosylation of α-dystroglycan, a receptor for laminin [2].

GPR56 is a member of the adhesion G protein-coupled receptor (GPCR) family. Mutations in GPR56 cause a specific human brain malformation called bilateral frontoparietal polymicrogyria (BFPP) [3][6]. The magnetic resonance images of BFPP brains revealed a thickened cerebral cortex with coarse gyri, shallow sulci, and a “scalloped” appearance at the grey-white matter junction – much like the radiological features of other polymicrogyria malformations. Histological analysis of Gpr56 knockout mouse brains and postmortem human BFPP brains revealed the histopathology of BFPP to be cobblestone lissencephaly [7], [8].

Collagen III is a major collagen found in connective tissues. Mutations in one allele of COL3A1 cause type IV EDS, an autosomal dominant connective tissue disorder [9][14]. Recently, we discovered that collagen III is the ligand of GPR56 [15]. In this paper, we carried out a detailed histological analysis of Col3a1−/− mouse brains. We found that the absence of collagen III results in a cobblestone-like cortical malformation.

Results

Cobblestone-like cortical malformation is associated with homozygous deletion of Col3a1

Although losing one allele of the Col3a1 gene is not associated with any obvious defects in mice, the effects of deleting both alleles is catastrophic [16]. Col3a1−/− usually results in perinatal lethality of an unknown etiology, with only 5% of mice reaching adulthood [16]. As for the surviving mice, their phenotype closely resembles the clinical manifestations of patients with type IV EDS, including the rupture of large blood vessels [16]. Due to the severity of this corresponding condition, the Col3a1−/− adult mice experience a signficantly shortened lifespan.

After discovering that collagen III serves as the major ligand of GPR56, we sought out to investigate the uncharacterized brain phenotype of Col3a1−/− mice. In order to discern the architecture of the cerebral cortex, we first performed Nissl stainings with a cresyl violet solution on the brains of E18.5 mice. All Col3a1−/− mice showed severe cortical malformation, manifested by the presence of neuronal ectopias on the brain surface (Figure 1 B–I). We next performed immunohistochemistry (IHC) using different layer markers to determine their neuronal composition and from where they first originated. Since over 95% of Col3a1−/− mice were lethal upon birth, we performed immunostainings on E18.5 brains [16]. We used three cortical layer-specific markers, Cux1 for layers II–IV, Tbr1 for layers II–III and VI and CTIP2 for layer V [17][19]. Neurons positive for Cux1, Tbr1 and CTIP2 were detected in the ectopias, suggesting that the ectopic cells in the Col3a1−/− cortex were neurons from both deep and superficial cortical layers, mirroring our observations of Gpr56 null mutant mice (Figure 2B, D and F) [8].

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Figure 1. Col3a1−/− mice have cortical abnormalities.

Sagittal sections from one Col3a1+/+ (A) and three Col3a1−/− forebrains (B–I) stained with Nissl. In contrast to the well-developed cortex in Col3a1+/+ brains (A), cortical malformation was seen in Col3a1−/− brains, characterized by the presence of ectopic clusters of neurons migrating into the marginal zone and disrupting the lamination of the cortex (B–I, arrowheads). Scale bar, 200 µm.

https://doi.org/10.1371/journal.pone.0029767.g001

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Figure 2. Cellular composition of Col3a1−/− cortical ectopias.

(A, B) Cux1 antibody immunostaining revealed that the ectopias were composed in part by upper layer cortical neurons inappropriately migrating through the marginal zone in Col3a1−/− brain (arrowheads). (C, D) Tbr1 immunostaining revealed that the deeper layer cortical neurons were also present in the ectopias of Col3a1−/− (arrowheads). (E, F) Layer V cortical neurons, revealed by CTIP2 immunostaining, that are normally localized to a discrete interior strip of cells were mislocalized in the ectopias of Col3a1−/− (arrowheads). Scale bar, 200 µm.

https://doi.org/10.1371/journal.pone.0029767.g002

The pial BM is properly formed but is subsequently disrupted in the Col3a1−/− mouse neocortex

To identify the leading pathology associated with Col3a1 deletion, we performed a detailed time course study of the occurrence of the breached pial BM and overmigrated neurons. While collagen III was expressed in the meninges and pial BM of Col3a1+/+ brains (Figure 3A, C, E, and G), the Col3a1−/− mice appeared to be true deletion mutants since collagen III was not present in either the meninges or the pial BM in brains ranging from E10.5–E14.5 (Figure 3B, D, F, and H). Interestingly, in spite of the absence of collagen III, the pial BM was initially properly formed at E10.5 in the mutant mice (Figure 3J). Regional breakdown of the pial BM with concurrent neuronal overmigration was observed in about half of the E11.5 and all embryos older than E12.5 in the Col3a1−/− brains analyzed (arrows, Figure 3L, N, P and Table 1).

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Figure 3. The pial BM is well formed at E10.5 but subsequently disrupted in the Col3a1−/− neocortex.

(A–H) Double IHC of Tuj1 and Collagen III in E10.5, E11.5, E12.5, and E14.5 brains. Collagen III was absent in all analyzed brains of Col3a1−/− mice. Tuj1+ migrating neurons (green) were well organized beneath the pial BM (red) in both Col3a1+/+ and Col3a1−/− at E10.5 (A and B), whereas Tuj1+migrating neurons (green) migrated past the pial BM into the arachnoid space (arrow) in the brains of Col3a1−/− mice at E11.5 and older (D, F, and H). (I–P) Double IHC of Tuj1 and laminin in E10.5, E11.5, E12.5, and E14.5 mouse brains. Tuj1+ neurons (green) were properly localized beneath the pial BM (red) in the brains of Col3a1+/+ mice at all embryonic days analyzed (I, K, M and O) and Col3a1−/− mouse at E10.5 (J). In contrast, ectopias were observed in the brains of Col3a1−/− mice from E11.5 through E14.5 (arrows, L, N, and P). Scale bar, 100 µm.

https://doi.org/10.1371/journal.pone.0029767.g003

Deleting Col3a1 results in abnormal attachment of radial glial endfeet

During normal brain development, radial glial endfeet attach to the pial BM and form an adhesive lining at the pial surface [20]. Since the proper attachment of the radial glial endfeet is relavent to the integrity of the pial BM, we therefore examined the arrangement of the endfeet in relationship to the pial BM by double IHC of nestin and laminin. At E10.5, radial glial endfeet were arranged in an orderly fashion along the intact pial BM in the brains of both Col3a1+/+ and Col3a1−/− mice (Figure 4A and B). We observed protruded endfeet through a breached pial BM in some of the E11.5 and all of the E12.5 Col3a1−/− brains (arrowheads, Figure 4D and F).

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Figure 4. Radial glial endfeet protrude into the ectopias of Col3a1−/− mice.

(A and B) Double IHC of nestin (green) and laminin (red) at E10.5 showed a parallel arrangement of fibers that terminated in well defined endfeet at the pial surface in both Col3a1+/+ (A) and Col3a1−/− mice (B). (C–F) Nestin+ radial glial endfeet (green) lined up nicely along the pial BM (red) in E11.5 and E12.5 Col3a1+/+ mice (C and E) but were abnormally located in the arachnoid space of ectopias in the region of breached pial BM (arrowheads) in Col3a1−/− mice (D and F). Scale bar, 100 µm.

https://doi.org/10.1371/journal.pone.0029767.g004

Loss of collagen III leads to abnormal positioning of both Cajal-Retzius (CR) cells and interneurons

There are two major neurons in the marginal zone of the developing neocortex – CR cells and interneurons. CR cells regulate the proper positioning of postmitotic neurons during cortical development by secreting reelin, an extracellular matrix (ECM) signaling molecule [21], [22]. To determine whether CR cells are abnormally located in the developing Col3a1−/− cortex, we compared the distribution of CR cells in brains of Col3a1+/+ and Col3a1−/− animals using reelin to identify CR cells. In contrast to the relatively continuous single layer of CR cells found at the marginal zone of E16.5 control animals (Figure 5A), we observed misplaced CR cells beyond the defective BM in Col3a1−/− brains (Figure 5B, arrowheads).

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Figure 5. Cajal-Retzius cells and interneurons are found in ectopias of Col3a1−/− mice.

(A and B) Double IHC of Reelin (green) and laminin (red) at E16.5 showed Reelin+ CR cells are lined up beneath the pial BM in Col3a1+/+ (A) but were located within the ectopia of Col3a1−/− mice (B, arrowheads). (C and D) Immunostaining of Calbindin (red) at E18.5. Calbindin+ interneurons are observed in the ectopias of Col3a1−/− mice (D, arrows) but were normally localized within the marginal zone and cortical plate in Col3a1+/+ brain (C). The pia surface of the brains is outlined in white. Nuclear counterstain was performed by Hoechst 33342 (blue). Scale bars, A and B, 100 µm; C and D, 200 µm.

https://doi.org/10.1371/journal.pone.0029767.g005

In order to investigate whether the migration of interneurons is affected by the loss of collagen III, we performed an IHC of calbindin in E18.5 brains of Col3a1 wild type and mutant mice. Calbindin+ interneurons were well organized beneath the pial BM in Col3a1+/+ brain (Figure 5C). In contrast, we detected calbindin+ interneurons in the ectopias of Col3a1−/− brains (Figure 5D, arrows).

MFs develop normally in the absence of collagen III

MFs are essential for basal lamina organization and cortical development, as defects in their proliferation and differentiation lead to cobblestone-like cortical malformation [23][25]. To study whether the loss of collagen III affects MF development, we studied the distribution of MFs in the Col3a1−/− mouse neocortex using a pan-Zic antibody that recognizes all Zic protein family members. Zic proteins are expressed in both MFs and CR cells at the surface of the developing brain [23]. To specifically reveal the status of MFs, we performed a double IHC of Zic with either reelin and Tuj1. The distribution of Zic+ cells in the meninges was comparable between Col3a1+/+ and Col3a1−/− brains in all stages evaluated, including the regions with neuronal ectopias (Figure 6A–H). To further examine the quality of Col3a1−/− MFs, we established a primary MF culture from the meninges of Col3a1+/+ and Col3a1−/− of E14.5 mice. The cell morphology and the pattern of laminin immunostaining were identical between Col3a1+/+ and Col3a1−/− MFs (Figure 6I and J).

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Figure 6. The MFs develop normally in Col3a1 mutant mice.

Double IHC of Zic (red) and Reelin (green) (A–D) or Tuj1 (green) (E–H) in Col3a1+/+ and Col3a1−/− brains revealed a normal distribution of Zic+ cells in all brains analyzed. (I and J) Laminin staining of primary MFs revealed no differences between Col3a1+/+ and Col3a1−/− mice. Nuclear counterstaining was performed by Hoechst 33342 (blue). Scale bars, A, B, E and F, I and J, 50 µm; C, D, G and H, 100 µm.

https://doi.org/10.1371/journal.pone.0029767.g006

α-Dystroglycan is not affected by Col3a1 deletion

Aberrant glycosylation of α-dystroglycan causes human cobblestone lissencephaly, whereas deleting the mouse Dag1 gene results in early embryonic lethality [1], [26], [27]. To investigate whether the signaling of GPR56 affects the expression and/or glycosylation status in the mouse developing brain, we performed IHC and western blot analysis with a monoclonal antibody that specifically detects the glycosylated form of α-dystroglycan in Col3a1 wild type and mutant mouse brains [28]. We failed to detect any change in the level of α-dystroglycan in the brains of Col3a1−/− mice, arguing that the function of collagen III does not directly affect the expression and glycosylation of dystroglycan (Figure 7).

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Figure 7. The expression of glycosylated α-Dystroglycan is not affected by loss of collagen III.

The level of glycosylated α-Dystroglycan revealed no change between Col3a1+/+ and Col3a1−/− E12.5 brains by IHC (A–B) and western blot analysis (C). Antibody IIH6C4 recognizes the glycosylated form of α-Dystroglycan. Scale bar, 50 µm.

https://doi.org/10.1371/journal.pone.0029767.g007

Discussion

We have shown that homozygous deletion of Col3a1 causes cobblestone-like cortical malformation characterized by pial BM breakdown, neuronal overmigration, radial glial detachment, and formation of marginal zone heterotopias. While the pial BM is established in the absence of collagen III, focal breaks of the pial BM with concurrent neuronal overmigration become obvious in later embryonic development.

In humans, cobblestone lissencephaly is typically seen in three types of congenital muscular dystrophy, namely WWS, MEB, and FCMD [1]. Although aberrant glycosylation of α-dystroglycan is the leading pathology of human cobblestone lissencephaly, we failed to detect any changes in the level of glycosylated α-dystroglycan in Col3a1−/− [26], [27]. This finding suggests that collagen III regulates cortical development independent of the dystroglycan pathway. Recent findings that mutations in COL4A1 cause an ocular/muscular/cortical developmental disorder in mice and WWS in humans without affecting the level of glycosylated α-dystroglycan further supports the heterogeneous etiology of cobblestone lissencephaly [29].

Mutant mice with deletions in some members of the integrin family as well as downstream associates of integrins, such as focal adhesion kinase (FAK) and integrin-linked kinase (Ilk) also show cortical migration defects with deficiencies in basal lamina integrity with features that resemble human cobblestone lissencephaly [30][37]. Moreover, it has been shown that GPR56 associates with tetraspanins CD9 and CD81 [38]. The function of this tetraspanin-GPR56 complex remains unclear. Members of the tetraspanin family of cell surface proteins act as molecular scaffolds with known adhesion proteins such as integrins to facilitate their function [39]. It is an intriguing question of whether the receptor-ligand pair of GPR56 and collagen III functions together with integrins in regulating cortical development.

On the surface of the brain lies the three layered meninges – the pia, the arachnoid, and the dura – in which the major cell type is MFs. It has been shown that cellular defects in MFs cause abnormal development of structures adjacent to the meninges, which are the skull and the brain. We have recently discovered that collagen III is expressed in abundance in the MFs [15]. However, we detected no obvious defects in the MFs of the Col3a1−/− mice, suggesting that the cortical dyslamination seen in Col3a1−/− mice is not the direct result of cellular defects of MFs, but rather the absence of collagen III, the ligand of GPR56.

EDS is a heterogeneous group of hereditary connective tissue disorders. Individuals with EDS present with joint and skin hyperextensibility and vascular problems, including aortic dissection and excessive bleeding [10][14]. There has been a reported association of EDS and periventricular heterotopia, which is characterized by the presence of nodules of neurons along the periventricular region of the brain [40]. Most reported cases of type IV EDS are associated with mutations in one allele of COL3A1 [14]. However, there is one reported case of recessive type IV EDS with homozygous mutation in COL3A1 gene and a diffuse cortical dysplasia, which was most prominent frontally [41]. We showed here that homozygous deletion of mouse Col3a1 results in perinatal lethality and cobblestone-like cortical malformation. It is possible that mutations in both alleles of COL3A1 associate with a lethal form of cobblestone lissencephaly similar to WWS.

Regulation of pial BM development and remodeling is likely to be dynamic and complex. The pial BM consists of thin sheets of proteins including laminins, collagen IV, nidogens, and perlecan. Collagen III is a type of fibrillar collagen that is thought to be mainly in the ECM of the skin, cardiac, and vascular tissues [42][45]. Although there is little knowledge of the presence of collagen III in the developing brain, our recent work confirmed the presence of collagen III in the pial BM by IHC and immunoelectron microscopy [15]. In this report, we revealed the indispensible function of collagen III in cortical development, setting the stage for further mechanistic study of how collagen III regulates brain development.

Materials and Methods

Ethics statement

Experiments were performed in accordance with National Institutes of Health guidelines for the care and use of laboratory animals, and with approval of the Animal Care and Use Committee of Children's Hospital Boston (approval ID: A3303-01).

Antibodies

The antibodies used in the study are peroxidase-conjugated goat anti-mouse IgG antibody (Sigma), rabbit anti-Englebreth-Holm-Swarm laminin (Sigma), rabbit anti-reelin (Chemicon International), mouse anti-Zic (gift from Dr. R. Segal), mouse and rabbit anti-Tuj1 (Covance), rabbit anti-human collagen III (Lifespan Biosciences), rabbit anti-calbindin (Swant), mouse anti-α-dystroglycan, II6C4 (Millipore), rabbit cux1 (a gift from C.A. Walsh, Children's Hospital Boston), rabbit anti-Tbr1 (a gift from R. Hevner, Seattle Children's Research Institute), rat anti-CTIP2 (Abcam), and mouse anti-nestin (BD Transduction Laboratories).

Mice

Col3a1 mice were obtained from the Jackson Laboratory with the strain name C.129S4(B6)-Col3a1tm1Jae/J in a BALB/c background as described previously [16]. Most of the homozygous mutant mice die at birth with only about 5% of them surviving to adulthood [16]. All breeding was carried out with heterozygote crossing.

Histology and immunohistochemistry (IHC)

Histology analysis was carried out as previously described [8], . Brains harvested from embryos were fixed using 4% paraformaldehyde and were cryoprotected by 30% sucrose. Brain sections obtained by cryostat were stained with 0.1% cresyl violet/0.5% acetic acid for Nissl staining. Sections were processed for immunostaining using standard procedures. Primary antibodies were visualized by appropriate fluorophore-conjugated secondary antibodies. Nuclei were stained with Hoechst 33342 (Invitrogen, 1∶2000). Images were captured using a Nikon 80i upright microscope. Representative photographs were obtained with the same exposure setting for control and mutant.

Preparation of mouse primary MFs and immunocytochemistry

Mouse primary MFs were established from the meninges of E14.5 Col3a1 wild type or mutant mice and amplified in DMEM with 10% FBS. MFs were cultured on poly-D-lysine (100 µg/ml) coated wells for 24 hours, followed by fixation with 4% paraformaldehyde. Cells were permeabilized with 0.1% Triton-X 100 in PBS for 10 minutes followed by incubation with anti-laminin antibody and visualized by goat anti-rabbit Alexa-Fluor 546 secondary antibody (Invitrogen). Hoechest 33342 (Invitrogen) was used for counter staining. Images were captured using a Nikon 80i upright microscope.

Acknowledgments

We would like to thank Drs. Christopher A. Walsh, Robert Hevner, and Rosalind A. Segal for providing antibodies.

Author Contributions

Conceived and designed the experiments: XP. Performed the experiments: SJ SL RL NS. Analyzed the data: SJ XP. Contributed reagents/materials/analysis tools: SJ NS. Wrote the paper: XP.

References

  1. 1. Olson EC, Walsh CA (2002) Smooth, rough and upside-down neocortical development. Curr Opin Genet Dev 12: 320–327.EC OlsonCA Walsh2002Smooth, rough and upside-down neocortical development.Curr Opin Genet Dev12320327
  2. 2. Barresi R, Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease. J Cell Sci 119: 199–207.R. BarresiKP Campbell2006Dystroglycan: from biosynthesis to pathogenesis of human disease.J Cell Sci119199207
  3. 3. Chang BS, Piao X, Bodell A, Basel-Vanagaite L, Straussberg R, et al. (2003) Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16. Ann Neurol 53: 596–606.BS ChangX. PiaoA. BodellL. Basel-VanagaiteR. Straussberg2003Bilateral frontoparietal polymicrogyria: clinical and radiological features in 10 families with linkage to chromosome 16.Ann Neurol53596606
  4. 4. Piao X, Basel-Vanagaite L, Straussberg R, Grant PE, Pugh EW, et al. (2002) An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q12.2-21. Am J Hum Genet 70: 1028–1033.X. PiaoL. Basel-VanagaiteR. StraussbergPE GrantEW Pugh2002An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to chromosome 16q12.2-21.Am J Hum Genet7010281033
  5. 5. Piao X, Chang BS, Bodell A, Woods K, Benzeev B, et al. (2005) Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann Neurol 58: 680–687.X. PiaoBS ChangA. BodellK. WoodsB. Benzeev2005Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes.Ann Neurol58680687
  6. 6. Piao X, Hill RS, Bodell A, Chang BS, Basel-Vanagaite L, et al. (2004) G protein-coupled receptor-dependent development of human frontal cortex. Science 303: 2033–2036.X. PiaoRS HillA. BodellBS ChangL. Basel-Vanagaite2004G protein-coupled receptor-dependent development of human frontal cortex.Science30320332036
  7. 7. Bahi-Buisson N, Poirier K, Boddaert N, Fallet-Bianco C, Specchio N, et al. (2010) GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex. Brain 133: 3194–3209.N. Bahi-BuissonK. PoirierN. BoddaertC. Fallet-BiancoN. Specchio2010GPR56-related bilateral frontoparietal polymicrogyria: further evidence for an overlap with the cobblestone complex.Brain13331943209
  8. 8. Li S, Jin Z, Koirala S, Bu L, Xu L, et al. (2008) GPR56 regulates pial basement membrane integrity and cortical lamination. J Neurosci 28: 5817–5826.S. LiZ. JinS. KoiralaL. BuL. Xu2008GPR56 regulates pial basement membrane integrity and cortical lamination.J Neurosci2858175826
  9. 9. Pope FM, Martin GR, Lichtenstein JR, Penttinen R, Gerson B, et al. (1975) Patients with Ehlers-Danlos syndrome type IV lack type III collagen. Proc Natl Acad Sci U S A 72: 1314–1316.FM PopeGR MartinJR LichtensteinR. PenttinenB. Gerson1975Patients with Ehlers-Danlos syndrome type IV lack type III collagen.Proc Natl Acad Sci U S A7213141316
  10. 10. Germain DP (2007) Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis 2: 32.DP Germain2007Ehlers-Danlos syndrome type IV.Orphanet J Rare Dis232
  11. 11. Kontusaari S, Tromp G, Kuivaniemi H, Romanic AM, Prockop DJ (1990) A mutation in the gene for type III procollagen (COL3A1) in a family with aortic aneurysms. J Clin Invest 86: 1465–1473.S. KontusaariG. TrompH. KuivaniemiAM RomanicDJ Prockop1990A mutation in the gene for type III procollagen (COL3A1) in a family with aortic aneurysms.J Clin Invest8614651473
  12. 12. Kuivaniemi H, Tromp G, Bergfeld WF, Kay M, Helm TN (1995) Ehlers-Danlos syndrome type IV: a single base substitution of the last nucleotide of exon 34 in COL3A1 leads to exon skipping. J Invest Dermatol 105: 352–356.H. KuivaniemiG. TrompWF BergfeldM. KayTN Helm1995Ehlers-Danlos syndrome type IV: a single base substitution of the last nucleotide of exon 34 in COL3A1 leads to exon skipping.J Invest Dermatol105352356
  13. 13. Prockop DJ, Kivirikko KI (1984) Heritable diseases of collagen. N Engl J Med 311: 376–386.DJ ProckopKI Kivirikko1984Heritable diseases of collagen.N Engl J Med311376386
  14. 14. Schwarze U, Schievink WI, Petty E, Jaff MR, Babovic-Vuksanovic D, et al. (2001) Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV. Am J Hum Genet 69: 989–1001.U. SchwarzeWI SchievinkE. PettyMR JaffD. Babovic-Vuksanovic2001Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV.Am J Hum Genet699891001
  15. 15. Luo R, Jeong SJ, Jin Z, Strokes N, Li S, et al. (2011) G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination. Proc Natl Acad Sci U S A 108: 12925–30.R. LuoSJ JeongZ. JinN. StrokesS. Li2011G protein-coupled receptor 56 and collagen III, a receptor-ligand pair, regulates cortical development and lamination.Proc Natl Acad Sci U S A1081292530
  16. 16. Liu X, Wu H, Byrne M, Krane S, Jaenisch R (1997) Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A 94: 1852–1856.X. LiuH. WuM. ByrneS. KraneR. Jaenisch1997Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development.Proc Natl Acad Sci U S A9418521856
  17. 17. Englund C, Fink A, Lau C, Pham D, Daza RA, et al. (2005) Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci 25: 247–251.C. EnglundA. FinkC. LauD. PhamRA Daza2005Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex.J Neurosci25247251
  18. 18. Molyneaux BJ, Arlotta P, Hirata T, Hibi M, Macklis JD (2005) Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47: 817–831.BJ MolyneauxP. ArlottaT. HirataM. HibiJD Macklis2005Fezl is required for the birth and specification of corticospinal motor neurons.Neuron47817831
  19. 19. Nieto M, Monuki ES, Tang H, Imitola J, Haubst N, et al. (2004) Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex. J Comp Neurol 479: 168–180.M. NietoES MonukiH. TangJ. ImitolaN. Haubst2004Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex.J Comp Neurol479168180
  20. 20. Rakic P (2003) Elusive radial glial cells: historical and evolutionary perspective. Glia 43: 19–32.P. Rakic2003Elusive radial glial cells: historical and evolutionary perspective.Glia431932
  21. 21. Tissir F, Goffinet AM (2003) Reelin and brain development. Nat Rev Neurosci 4: 496–505.F. TissirAM Goffinet2003Reelin and brain development.Nat Rev Neurosci4496505
  22. 22. Rice DS, Curran T (2001) Role of the reelin signaling pathway in central nervous system development. Annu Rev Neurosci 24: 1005–1039.DS RiceT. Curran2001Role of the reelin signaling pathway in central nervous system development.Annu Rev Neurosci2410051039
  23. 23. Inoue T, Ogawa M, Mikoshiba K, Aruga J (2008) Zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type II lissencephaly. J Neurosci 28: 4712–4725.T. InoueM. OgawaK. MikoshibaJ. Aruga2008Zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type II lissencephaly.J Neurosci2847124725
  24. 24. Sievers J, Pehlemann FW, Gude S, Berry M (1994) Meningeal cells organize the superficial glia limitans of the cerebellum and produce components of both the interstitial matrix and the basement membrane. J Neurocytol 23: 135–149.J. SieversFW PehlemannS. GudeM. Berry1994Meningeal cells organize the superficial glia limitans of the cerebellum and produce components of both the interstitial matrix and the basement membrane.J Neurocytol23135149
  25. 25. Zarbalis K, Siegenthaler JA, Choe Y, May SR, Peterson AS, et al. (2007) Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development. Proc Natl Acad Sci U S A 104: 14002–14007.K. ZarbalisJA SiegenthalerY. ChoeSR MayAS Peterson2007Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development.Proc Natl Acad Sci U S A1041400214007
  26. 26. Henry MD, Campbell KP (1998) A role for dystroglycan in basement membrane assembly. Cell 95: 859–870.MD HenryKP Campbell1998A role for dystroglycan in basement membrane assembly.Cell95859870
  27. 27. Williamson RA, Henry MD, Daniels KJ, Hrstka RF, Lee JC, et al. (1997) Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice. Hum Mol Genet 6: 831–841.RA WilliamsonMD HenryKJ DanielsRF HrstkaJC Lee1997Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice.Hum Mol Genet6831841
  28. 28. Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, et al. (2002) Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418: 417–422.DE MicheleR. BarresiM. KanagawaF. SaitoRD Cohn2002Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies.Nature418417422
  29. 29. Labelle-Dumais C, Dilworth DJ, Harrington EP, de Leau M, Lyons D, et al. (2011) COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans. PLoS Genet 7: e1002062.C. Labelle-DumaisDJ DilworthEP HarringtonM. de LeauD. Lyons2011COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans.PLoS Genet7e1002062
  30. 30. Georges-Labouesse E, Mark M, Messaddeq N, Gansmuller A (1998) Essential role of alpha 6 integrins in cortical and retinal lamination. Curr Biol 8: 983–986.E. Georges-LabouesseM. MarkN. MessaddeqA. Gansmuller1998Essential role of alpha 6 integrins in cortical and retinal lamination.Curr Biol8983986
  31. 31. De Arcangelis A, Mark M, Kreidberg J, Sorokin L, Georges-Labouesse E (1999) Synergistic activities of alpha3 and alpha6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse. Development 126: 3957–3968.A. De ArcangelisM. MarkJ. KreidbergL. SorokinE. Georges-Labouesse1999Synergistic activities of alpha3 and alpha6 integrins are required during apical ectodermal ridge formation and organogenesis in the mouse.Development12639573968
  32. 32. Graus-Porta D, Blaess S, Senften M, Littlewood-Evans A, Damsky C, et al. (2001) Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex. Neuron 31: 367–379.D. Graus-PortaS. BlaessM. SenftenA. Littlewood-EvansC. Damsky2001Beta1-class integrins regulate the development of laminae and folia in the cerebral and cerebellar cortex.Neuron31367379
  33. 33. Halfter W, Dong S, Yip YP, Willem M, Mayer U (2002) A critical function of the pial basement membrane in cortical histogenesis. J Neurosci 22: 6029–6040.W. HalfterS. DongYP YipM. WillemU. Mayer2002A critical function of the pial basement membrane in cortical histogenesis.J Neurosci2260296040
  34. 34. Beggs HE, Schahin-Reed D, Zang K, Goebbels S, Nave KA, et al. (2003) FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Neuron 40: 501–514.HE BeggsD. Schahin-ReedK. ZangS. GoebbelsKA Nave2003FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies.Neuron40501514
  35. 35. Niewmierzycka A, Mills J, St-Arnaud R, Dedhar S, Reichardt LF (2005) Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly. J Neurosci 25: 7022–7031.A. NiewmierzyckaJ. MillsR. St-ArnaudS. DedharLF Reichardt2005Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly.J Neurosci2570227031
  36. 36. Haubst N, Georges-Labouesse E, De Arcangelis A, Mayer U, Gotz M (2006) Basement membrane attachment is dispensable for radial glial cell fate and for proliferation, but affects positioning of neuronal subtypes. Development 133: 3245–3254.N. HaubstE. Georges-LabouesseA. De ArcangelisU. MayerM. Gotz2006Basement membrane attachment is dispensable for radial glial cell fate and for proliferation, but affects positioning of neuronal subtypes.Development13332453254
  37. 37. Costell M, Gustafsson E, Aszodi A, Morgelin M, Bloch W, et al. (1999) Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 147: 1109–1122.M. CostellE. GustafssonA. AszodiM. MorgelinW. Bloch1999Perlecan maintains the integrity of cartilage and some basement membranes.J Cell Biol14711091122
  38. 38. Little KD, Hemler ME, Stipp CS (2004) Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Galpha q/11 association. Mol Biol Cell 15: 2375–2387.KD LittleME HemlerCS Stipp2004Dynamic regulation of a GPCR-tetraspanin-G protein complex on intact cells: central role of CD81 in facilitating GPR56-Galpha q/11 association.Mol Biol Cell1523752387
  39. 39. Levy S, Shoham T (2005) The tetraspanin web modulates immune-signalling complexes. Nat Rev Immunol 5: 136–148.S. LevyT. Shoham2005The tetraspanin web modulates immune-signalling complexes.Nat Rev Immunol5136148
  40. 40. Parrini E, Ramazzotti A, Dobyns WB, Mei D, Moro F, et al. (2006) Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Brain 129: 1892–1906.E. ParriniA. RamazzottiWB DobynsD. MeiF. Moro2006Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations.Brain12918921906
  41. 41. Plancke A, Holder-Espinasse M, Rigau V, Manouvrier S, Claustres M, et al. (2009) Homozygosity for a null allele of COL3A1 results in recessive Ehlers-Danlos syndrome. Eur J Hum Genet 17: 1411–1416.A. PlanckeM. Holder-EspinasseV. RigauS. ManouvrierM. Claustres2009Homozygosity for a null allele of COL3A1 results in recessive Ehlers-Danlos syndrome.Eur J Hum Genet1714111416
  42. 42. Vuorio E, de Crombrugghe B (1990) The family of collagen genes. Annu Rev Biochem 59: 837–872.E. VuorioB. de Crombrugghe1990The family of collagen genes.Annu Rev Biochem59837872
  43. 43. Piezzi RS, Guzman JA, Pelzer LE, Scardapane L, Dominguez S (1984) Biological role of the pineal. Responses to the environmental photoperiod. Arch Biol Med Exp (Santiago) 17: 273–282.RS PiezziJA GuzmanLE PelzerL. ScardapaneS. Dominguez1984Biological role of the pineal. Responses to the environmental photoperiod.Arch Biol Med Exp (Santiago)17273282
  44. 44. Epstein EH Jr, Munderloh NH (1975) Isolation and characterization of CNBr peptides of human (alpha 1 (III))3 collagen and tissue distribution of (alpha 1 (I))2 alpha 2 and (alpha 1 (III))3 collagens. J Biol Chem 250: 9304–9312.EH Epstein JrNH Munderloh1975Isolation and characterization of CNBr peptides of human (alpha 1 (III))3 collagen and tissue distribution of (alpha 1 (I))2 alpha 2 and (alpha 1 (III))3 collagens.J Biol Chem25093049312
  45. 45. Bornstein P, Sage H (1980) Structurally distinct collagen types. Annu Rev Biochem 49: 957–1003.P. BornsteinH. Sage1980Structurally distinct collagen types.Annu Rev Biochem499571003