Human Molecular Genetics, 2000, Vol. 9, No. 20 3083-3090
© 2000 Oxford University Press
Neuronal expression of the fukutin gene
1Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan, 2Laboratory of Genome Medicine and 3Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, 4Department of Neurology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8519, Japan, 5Department of Pediatrics and 6Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan and 7Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan
Received 29 August 2000; Revised and Accepted 4 October 2000.
DDBJ/EMBL/GenBank accession no. AB008226.
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ABSTRACT |
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Fukuyama-type congenital muscular dystrophy (FCMD), a relatively common autosomal recessive disorder in Japan, is characterized by severe congenital muscular dystrophy in combination with cortical dysgenesis (polymicrogyria). The gene responsible for FCMD encodes a novel protein, fukutin, which is likely to be an extracellular protein. Pathological study of brain tissue from FCMD fetuses revealed frequent breaks in the glia limitans and basement membrane complex. Disruption of the basal lamina in FCMD muscle was also seen. Thus, structural alteration of the basal lamina appears to play a key role in the pathophysiology of FCMD. To investigate the role of fukutin in brain anomalies, we examined fukutin mRNA expression in the human brain. Northern blot and RT–PCR analysis revealed that the fukutin gene is expressed at similar levels in fetal and adult brain, whereas its expression is much reduced in FCMD brains. Tissue in situ hybridization analysis revealed fukutin mRNA expression in the migrating neurons, including Cajar–Retzius cells and adult cortical neurons, as well as in hippocampal pyramidal cells and cerebellar Purkinje cells. However, we observed no expression in the glia limitans, the subpial astrocytes (which contribute to basement membrane formation) or other glial cells. In the FCMD brain, neurons in regions with no dysplasia showed fair expression, whereas transcripts were nearly undetectable in the overmigrated dysplastic region. These observations suggest that fukutin function may influence neuronal migration itself rather than formation of the basement membrane. Furthermore, differences in mRNA levels among neurons in early developmental stages may partially differentiate normal and abnormal regions.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Fukuyama-type congenital muscular dystrophy (FCMD; MIM 253800) is the second most common muscular dystrophy in Japan. An autosomal recessive disorder, FCMD is characterized by severe congenital muscular dystrophy associated with brain malformation, principally cerebral and cerebellar cortical dysplasia (1,2). Functional disability is more severe in FCMD patients than in Duchenne muscular dystrophy patients; usually, the maximum level of motor function achieved is unassisted sitting or sliding on the buttocks. Intellectual, cognitive and communicative functions are moderately delayed. The most common brain anomaly is polymicrogyria (type II lissencephaly) that lacks neuronal lamination in the normal six-layered cortex. Focal interhemispheric fusion, fibroglial proliferation of the leptomeninges, mild to moderate ventricular dilation and hypoplasia of the corticospinal tracts are also often observed (3). Finally, ophthalmological findings such as retinal dysplasia or microphthalmia are occasionally observed in FCMD patients (4). Thus, FCMD is a multi-systemic disease that involves muscle, eye and brain.
We previously identified the FCMD gene on chromosome 9q31 by positional cloning (5–7). Most FCMD-bearing chromosomes (87%) are derived from a single ancestral founder and have a 3 kb retrotransposal insertion into the 3' non-coding region of the FCMD gene. This insertion causes a significant reduction in the corresponding mRNA and is thought to cause the FCMD phenotype due to loss of function (7). Through systematic mutational analysis of 107 unrelated FCMD families, we identified several non-founder mutations (point mutations that generate primarily nonsense and frameshift mutations) existing as compound heterozygous with the founder insertion. Genotype–phenotype analysis revealed typical or mild phenotypes in patients homozygous for the founder retrotransposal insertion. In contrast, more severe phenotypes, including Walker–Warburg syndrome-like manifestations such as microphthalmia and hydrocephalus, were observed in patients carrying non-founder mutations, which are likely to produce structural changes in the protein product rather than a reduction in mRNA levels. We identified no FCMD patients homozygous for non-founder mutations, suggesting that such cases might be embryonic lethal (8).
Fukutin is a protein of 461 amino acids with a predicted molecular weight of 53.7 kDa. A novel protein of unknown function, fukutin contains an N-terminal hydrophobic signal sequence but lacks a transmembrane domain or organelle sorting signals. Transfection experiments indicated that fukutin protein is transferred to an extracellular region, colocalizing with a Golgi protein. These observations indicated that fukutin is likely to be an extracellular protein (7).
Histopathological analyses have suggested a potential role for fukutin in formation of the basement membrane. Secondary reduction of laminin 
2 chain (9), an extracellular matrix protein, has been observed in FCMD muscle. Electron microscopy has revealed basal lamina abnormalities in FCMD muscle (10). Moreover, pathological study of brain tissue from FCMD fetuses has revealed frequent breaches in the glia limitans and basement membrane complex (11–13). Developing neurons were shown to overmigrate through these breaches into the subarachnoid space, which may result in the lack of a six-layered cortex. Similar breaches were seen in adult FCMD brain tissue (14).
To further investigate the contributions of fukutin mutations to anomaly formation, we have compared fukutin gene expression in control and FCMD brains at various stages of development.
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RESULTS |
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We examined fukutin gene expression in control and FCMD human brain tissues using northern blot analysis, RT–PCR amplification and tissue in situ hybridization (Table 1). Northern blot analysis showed relatively equivalent levels of fukutin gene expression in various fetal tissues and adult brain regions (Fig. 1a). Figure 1b shows the results of RT–PCR amplification of fukutin mRNA. Expression was detected in human embryonic cortices showing early neuronal migration and continued to adulthood. In FCMD brain samples, fukutin expression was greatly reduced at various ages compared with control subjects. Fukutin mRNA levels in cultured neuronal cell lines were considerably higher than those in glial cell lines, which showed nearly undetectable levels of expression.
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To examine expression profiles of fukutin mRNA in various cell types, we analyzed normal human cerebral and cerebellar tissues at various ages using in situ hybridization. Control tissue samples for in situ hybridization analysis came from five fetuses aged 10, 19, 28, 32 and 40 gestational weeks and three individuals aged 11, 31 and 70 years. Hybridization with the antisense probe produced a significant signal, whereas no signal was observed in sections hybridized with the sense probe. Figure 2a shows a microscopic view of a cerebral coronal section from a 10-week-old fetus hybridized with the fukutin antisense RNA probe. Intense hybridization signal was detected in the cell body of neuronal cells, including precursor neurons in the ventricular layer, neurons migrating through the intermediate layer, cortical neurons and Cajar–Retzius cells. Migrating neurons were stained like orientated chains. At 28 weeks, neurons in the cortical plate and Cajar–Retzius cells in the marginal layer were strongly stained (Fig. 2b). The Cajar–Retzius cells of layer I showed typical morphology (i.e. triangular or inverted pyramidal cell bodies). More importantly, however, fukutin expression was not observed in the glia limitans, the subpial astrocytes (which produce the basement membrane) or other glial cells. Examination of cerebellar cortex from a 19-week-old fetus revealed particularly strong expression in external granule cells and also in internal granule cells and Purkinje cells (Fig. 2c).
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Macroscopic views of cerebral sections also provided evidence for higher fukutin expression in the cortex than in the white matter. As shown in Figure 3a, fukutin expression was seen in postnatal cortical neurons on the surface of the frontal cortex at 11 years of age. In contrast, the fukutin gene was not expressed in the glia limitans and subpial astrocytes that stained positive with anti-GFAP antibody (Fig. 3b). Also, fukutin expression was almost undetectable in other glial cells located in the white matter.
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Various types of neuron throughout the brain showed equally intense hybridization signals. Expression was detected in hippocampal pyramidal cells and granule cells of the dentate gyrus (Fig. 3c). Cerebellar Purkinje cells stained strongly, and cerebellar granular cells (Fig. 3d) as well as neurons in the cerebellar dentate nucleus (data not shown) also showed staining.
We further compared fukutin mRNA expression between control and FCMD individuals. We observed significant differences in fukutin mRNA levels between the region showing a pathological change and the intact region in the FCMD cerebrum. Figure 4a shows a wide view of cerebral sagittal sections from control and FCMD individuals at 19 weeks. In the FCMD brain, cortical neurons in the region without dysplasia exhibited weaker but detectable staining, whereas staining was nearly undetectable in the overmigrated dysplastic region. Moderate expression levels were observed in the hippocampal neurons, which are the least affected in the FCMD brain. Figure 4b shows a focussed view of the boundary region. In areas of the boundary that have no dysplasia, cortical plate neurons show continuous fukutin mRNA expression, but the signal is weak compared with controls. Conversely, no staining is seen in neurons within the overmigrated abnormal region.
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DISCUSSION |
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During development, the human cerebral hemisphere is subdivided into several embryonic layers. Mitotic precursor neurons are localized in the ventricular layer adjacent to the lateral ventricle (15). The deployment of radial glia, the formation of the glia limitans, the establishment of the pial–glial barrier and the migration and maturation of Cajar–Retzius neurons within the marginal layer all take place by 6 weeks (16). Postmitotic neurons derived from neuroblasts migrate tangentially to the surface along radial glial fibers and they form cortical plates 7 weeks after ovulation (17). The intermediate layer consists of several rows of postmitotic cells that appear peripheral to the ventricular layer. Migrating neurons encounter reelin protein, expressed on the surface of Cajal–Retzius cells, then detach from the fiber, land in their final positions and establish synaptic contacts (18). The cortical cell population is fed by continued cell proliferation in the ventricular layer. Autoradiographic studies have shown that the cortical layers develop in the inside-out direction. Neuronal migration ends at
34 weeks; subsequently, the generative ventricular layer disappears, leaving a differentiated ependymal layer. The intermediate zone becomes the definitive white matter (17). Detailed molecular mechanisms of neuronal migration and corticogenesis have not been established. On the contrary, cellular production in cerebellum arises primarily from the rhombic lip of rhombomere 1 and the ventricular layer of the alar laminae. Cells migrating externally from the ventricular layer give rise to the Purkinje cells and cells for the deep nuclei. Those from the rhombic lip form the external granular layer, from which cells migrate internally and form the internal granular layer (19,20).
In this study, we have demonstrated that fukutin mRNA is expressed specifically in neuronal cell lineages but not in glial cells within the prenatal developing human cerebrum and cerebellum. Intense hybridization signal was detected in the cell bodies of precursor neurons in the ventricular layer, neurons migrating through the intermediate layer, cortical neurons and Cajar–Retzius cells. In the cerebellum, the fukutin gene was expressed specifically in external granule cells as well as in internal granule cells and Purkinje cells and in neurons within the dentate nucleus. In the postnatal human cerebrum, high levels of fukutin mRNA expression was detected in cortical neurons and other neuronal cell types, such as hippocampal pyramidal cells and granule cells.
The glia limitans–basement membrane complex appears to be critical to the migration and final positioning of neurons. In the brain, the basement membrane is observed in the boundary between nervous tissue and leptomeninges, or blood vessels. Ultrastructurally, the basement membrane is formed on the surface of astrocytic endfeet beneath the pia. From a structural standpoint, astrocytes and mesenchymal cells, including leptomeninges and vessels, appear to be most likely to produce basement membrane-related proteins in the brain (21,22).
Following the localization of the gene responsible for FCMD, histological studies of the brains of mid-gestation fetuses with a prenatal genetic diagnosis of FCMD were reported (11–13). The cerebrum of the FCMD fetus had widespread neurogliomesenchymal tissue in the region showing breaches in the glia limitans and basal lamina; the cortical area with an intact glia limitans and basal lamina was totally free of these abnormal features. The dysplastic region borders the adjacent normal cortex (11). In the cerebellum of the FCMD fetus, external granular cells escaped toward the subarachnoid space with breaches in the glia limitans and basal lamina (3). Also, in FCMD individuals after birth, the basal lamina of the cortical surface was breached with protruding neural tissue of polymicrogyria and partly with gyral adhesion (14). These findings implied that breaches in the glia limitans and basal lamina may be the primary cause of the polymicrogyria seen in FCMD and that the fukutin gene product participates in development of the glia limitans or basal lamina.
Our investigation has localized expression of the fukutin gene primarily to neurons, which are not involved in the formation of the basement membrane. Furthermore, fukutin was not expressed in the glia limitans–basement membrane complex, the subpial astrocytes (which produce the basement membrane) or other glial cells. These observations suggest that fukutin may instead play a role in neuronal migration itself rather than in basement membrane formation.
In the FCMD fetal brain, fukutin mRNA expression in neurons was generally lower than that in control subjects. Furthermore, in the overmigrated dysplastic region the positive signal was nearly undetectable, whereas cortical neurons in the region without dysplasia showed weaker but continuous expression. Thus, we have documented significant differences in fukutin mRNA level between regions showing pathological changes and intact regions in the FCMD cerebrum, particularly in the cortical plate, although the problem remains that these data are based on the analysis of a single fetal patient sample.
Northern blot analysis of poly(A) mRNA from several FCMD individuals showed a similar reduction in fukutin gene expression in FCMD individuals who were homozygous or compound heterozygous for the ancestral founder insertion compared with controls. Because the insertion occurs in the 3' untranslated region, it is likely that the stability of fukutin mRNA is reduced through alteration of secondary structure (7). Together, these observations point to a correlation between the levels of fukutin mRNA and the cortical dysplasia associated with FCMD. Moreover, differences in mRNA amount among neurons during early stages of development may partially discriminate between the normal and abnormal area.
In addition to fukutin, several other genes involved in neuronal migration disorders have recently been cloned. These include reelin from the reeler mouse (23), mdab1 in the scrambler and yotari mice (24,25), LIS1 in Miller–Dieker syndrome and isolated lissencephaly sequence (26), doublecortin in X-linked lissencephaly in males and subcortical laminar heterotopia in females (27,28) and EMX-2 in familial schizencephaly (29). During the fetal period, reelin is expressed in Cajar–Retzius cells in the cerebrum and external granular cells in the cerebellum (18,23). Reelin protein, which possesses an EGF-like motif but has no transmembrane domain, shares sequence similarity with adhesion molecules and other extracellular matrix proteins (30). Reelin protein is involved in the arrest of locomotion and final positioning of migrating neurons along glial fibers (18). Like reelin, the fukutin gene is expressed in the Cajar–Retzius cells but does not appear to be expressed in radial fibers; also, fukutin protein is a putative secreted extracellular matrix molecule. Unlike reelin, however, the fukutin gene is expressed in all developmental neurons, including precursor neurons, migrating neurons and cortical neurons. Fukutin expression continues after birth, suggesting a potential role for fukutin in neuronal migration and other neuronal functions.
Very recently, Saito et al. (31) raised antisera against fukutin and observed its expression in normal human brain tissue. According to this study, fukutin antisera detected a 60 kDa protein band whose expression was markedly reduced in postnatal normal brain. These results contrast with our observation of similar levels of fukutin mRNA expression in prenatal, neonatal and adult normal brain. Differences in observed expression levels may reflect the higher specificity of hybridization by nucleic acids than that of epitope recognition by an antibody. Further study will help in delineating expression patterns of fukutin mRNA and protein during various stages of human brain development, as well as shedding additional light on the mechanism of fukutin function in brain development.
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MATERIALS AND METHODS |
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Tissues
For RT–PCR analysis, brain tissue from four FCMD individuals and four neurologically normal controls was obtained at autopsy within 24 h post mortem. Tissue samples were immediately frozen and stored at –80°C. FCMD individuals include a 14-week-old fetus that was homozygous for the retrotransposal insertion, a 19-week-old fetus that was compound heterozygous for the insertion and an exon 3 nonsense mutation and two adult females, aged 19 and 22 years, who were homozygous for the founder insertion. Control subjects were two fetuses (14 and 19 weeks), one child (11 years) and one adult (31 years).
For in situ hybridization analysis, brain tissues containing frontal lobe, temporal lobe, hippocampus and cerebellum were obtained within 24 h post mortem from two individuals with FCMD (a 19-week-old fetus and a 19-year-old female) and eight neurologically normal controls. Control subjects include five fetuses (10, 19, 28, 32 and 40 weeks), one child (11 years) and two adults (31 and 70 years). Brain samples were fixed in 10% buffered formalin, embedded in paraffin, cut into 6 µm thick sections and placed onto silane-coated slides under RNase free conditions. Control subjects (aged 19 weeks, 11 and 31 years) and FCMD individuals (aged 19 weeks and 19 years) were the same as those used for RT–PCR. Gestational age is represented here as total weeks from the last menstrual period. Therefore, gestational age may be 2 weeks greater than the actual conceptional (post-ovulatory) embryonic age.
Cell lines
Glioblastoma cell lines T98G and SW1783 and the neuroblastoma cell line IMR-32 were purchased from the American Type Culture Collection (Manassas, VA). hNT neurons, which were derived from a teratocarcinoma cell line NT2 cells by treatment with retinoic acid and mitotic inhibitors, were purchased from Stratagene (La Jolla, CA).
Northern blot analysis
A human fetal multiple tissue northern blot and a human adult brain multiple tissue northern blot containing 2 µg of poly(A)+ RNA from each human tissue (Clontech, Palo Alto, CA) were hybridized with FCMD cDNA (clone II-5) and ß-actin cDNA probes that were radiolabeled with [-32P]dCTP using the Megaprime labeling kit (Amersham Pharmacia, Little Chalfont, UK) in 50% formamide, 2% SDS, 10x Denhart, 5x SSPE, 100 µg/ml salmon sperm DNA at 42°C. Blots were washed in 0.1x SSC and 0.1% SDS at 50°C.
RNA extraction and RT–PCR
Total RNA was isolated from neurologically normal and FCMD cortices and neuronal and glial cell lines with TRIzol reagent (Gibco BRL, Rockville, MD). In each RT–PCR reaction, 5 µg of total RNA was used as a template and was reverse transcribed with a SuperScript II pre-amplification kit (Gibco BRL).
Primers used for PCR amplification were 1.11F (5'-CTTCTCATGGCTCTACTTCAC-3') in FCMD exon 4 and 1R (5'-TGAAAGACTACCAAGTGGATC-3') in exon 5, which produce a 253 bp fragment. The primers for glyceraldehyde 3-phosphate (GAPDH), GAPDH-F (5'-CAACTACATGGTTTACATGTTC-3') and GAPDH-R (5'-GCCAGTGGACTCCACGAC-3'), were used for comparative expression analysis. PCR reactions were performed in a 25 µl reaction mixture containing FCMD or GAPDH primers (25 pmol each), dNTPs (0.2 µM each) and 0.5 U EX Taq DNA polymerase (TaKaRa, Kyoto, Japan). A Perkin Elmer (Foster City, CA) model 9700 thermal cycler was used for amplification (28 cycles for the FCMD gene and 23 cycles for GAPDH), under the following conditions: denaturation, 94°C for 30 s; annealing, 55°C for 30 s; and extension, 72°C for 1 min. PCR products were separated electrophoretically on 2.5% agarose gels and visualized by staining with ethidium bromide.
In situ hybridization
In situ hybridization analysis was performed as described (32). Briefly, RNA probes were prepared using various FCMD cDNA clones (pBluescript II). Antisense and sense RNA probes were synthesized using T7 and T3 RNA polymerases and a digoxigenin (DIG) RNA labeling kit (Boehringer Mannheim, Mannheim, Germany) according to the manufacturer’s instructions. A sense-strand RNA probe was used as a negative control. Probes were fragmented to 160 bp using an alkaline solution. A total of eight antisense probes covering the entire cDNA sequence were prepared and the most specific probe (p
Xba1, sequence positions 3708–4593) was selected by dot blot hybridization.
After deparaffinization with xylene and treatment with proteinase K (20 µg/ml) for 30 min at 37°C, brain sections were hybridized at 55°C in hybridization buffer (50% formamide, 5x SSC, 1% SDS, 50 µg/ml yeast tRNA, 50 µg/ml heparin) and washed with 50% formamide and 2x SSC solution at 55°C, followed by RNase A treatment (25 µg/ml) at room temperature for 45 min. Hybridized probes were detected with an alkaline phosphatase-labeled anti-DIG antibody and visualized with 4-nitro blue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate.
Immunohistochemistry
A rabbit polyclonal antibody against glial fibrillary acidic protein (GFAP) (1:2000; Dako, Santa Barbara, CA) was used to identify radial glia and astrocytes in immunohistochemical assays.
All brain sections were treated with 0.3% hydrogen peroxide in methanol for 20 min to block endogenous peroxidase activity. After pretreatment, sections were incubated with anti-rabbit GFAP antibody for 30 min at room temperature. Detection was performed using the avidin–biotinylated peroxidase complex (ABC) method (Histofine SAB-PO kit; Nichirei, Tokyo, Japan) and developed with diaminobenzidine. Slides were counterstained with hematoxylin.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge Dr H. Saegusa for advice. We are also grateful to K. Iwasawa, S. Inada and Y. Nakajima for technical assistance. This work was supported by a Health Science Research Grant, ‘Research on Brain Science’ (H10-Brain-024) and by a Research Grant for Nervous and Mental Disorders (11B-1), both from the Ministry of Health and Welfare, Japan, and also by a Grant-in-Aid for Science Research on Priority Areas from the Ministry of Education, Science, Sports and Culture, Japan.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +81 6 6879 3380; Fax: +81 6 6879 3389; Email: toda@clgene.med.osaka-u.ac.jp
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REFERENCES |
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