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PubMed2003

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex.

Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.

ADP-Ribosylation Factors↗
PubMed2006

Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis.

The mitochondrial protein apoptosis-inducing factor (AIF) translocates to the nucleus and induces apoptosis. Recent studies, however, have indicated the importance of AIF for survival in mitochondria. In the absence of a means to dissociate these two functions, the precise roles of AIF remain unclear. Here, we dissociate these dual roles using mitochondrially anchored AIF that cannot be released during apoptosis. Forebrain-specific AIF null (tel. AifDelta) mice have defective cortical development and reduced neuronal survival due to defects in mitochondrial respiration. Mitochondria in AIF deficient neurons are fragmented with aberrant cristae, indicating a novel role of AIF in controlling mitochondrial structure. While tel. AifDelta Apaf1(-/-) neurons remain sensitive to DNA damage, mitochondrially anchored AIF expression in these cells significantly enhanced survival. AIF mutants that cannot translocate into nucleus failed to induce cell death. These results indicate that the proapoptotic role of AIF can be uncoupled from its physiological function. Cell death induced by AIF is through its proapoptotic activity once it is translocated to the nucleus, not due to the loss of AIF from the mitochondria.

Adenosine Triphosphate↗
PubMed2004

The reelin pathway components disabled-1 and p35 in gangliogliomas--a mutation and expression analysis.

Focal epilepsies in young patients are frequently associated with differentiated glioneuronal tumours. Dysplastic neurones represent a characteristic neuropathological feature of gangliogliomas, the most common entity encountered in this group. Here, we have analysed two major components of the reelin pathway involved in neuronal migration and cortical development, that is, p35 and disabled-1 (dab1), in gangliogliomas. Genomic structures of human dab1 and p35 were identified 'in silico' using the HTGS databank, NCBI BLAST 2.1. DNA sequence analysis was carried out in gangliogliomas obtained from 29 epilepsy patients vs. peripheral blood DNA from non-affected control individuals (n = 100). Gene expression of dab1 and p35 was determined by real-time RT-PCR (reverse transcriptase polymerase chain reaction) in gangliogliomas (n = 14) vs. non-neoplastic central nervous system tissue (n = 20). The human dab1 gene contains 13 coding exons and is located on chromosome 1p31-32. A single coding exon constitutes the human p35 gene, which is located on chromosome 17q11.2. A novel homologueous genomic region on chromosome 2 has to be taken into account for future studies on p35. One ganglioglioma patient showed a unique polymorphism in the p35 gene. The single base exchange (C to A) at nucleotide 904 of the p35 cDNA (GenBank X80343, start ATG, codon 302) results in a leucine-isoleucine amino acid substitution. No mutations of the dab1 and p35 genes in gangliogliomas were observed. However, significantly lower levels of dab1 and p35 gene transcripts were detected in gangliogliomas compared to controls (dab1 28.24%, t-test P < 0.001; p35 21.28%, t-test P < 0.001, in gangliogliomas vs. controls). Our data suggest that mutational events of dab1 and p35 are not involved in the molecular pathogenesis of gangliogliomas. A potential functional role of these developmentally regulated genes for the formation of epileptogenic glioneuronal lesions remains to be elucidated.

Adaptor Proteins, Signal Transducing↗
PubMed1999

A descriptive survey of long-term residents with epilepsy and intellectual disability at the Chalfont Centre: is there a relationship between maladaptive behaviour and magnetic resonance imaging findings?

The advent of high-resolution magnetic resonance imaging (MRI) has facilitated the identification of subtle, aetiologically relevant structural brain abnormalities in a significant proportion of patients with epilepsy and negative standard neuro-imaging. In the present study of people with intellectual disability (ID), the authors show that a high frequency of cerebral structural abnormalities (72.4%) can be demonstrated by high-resolution MRI in patients with epilepsy and ID. Malformations of cortical development (MCD) were found in 8.7% of people without profound ID. An earlier age of onset of habitual seizures was associated with more severe ID and more severe seizures in adulthood. There was no obvious association between this finding and maladaptive behaviour, but a past history of febrile convulsions was associated with increased irritability and agitation. Since there was no obvious association between a history of febrile convulsions and MRI abnormalities, the reason for the above finding remains unclear. Inevitably, any residential epilepsy centre population is subject to selection biases. The population studied was highly skewed, with only one-third of the sample being female and 80% having mild ID. Thus, the findings of the present study cannot necessarily be generalized to all people with ID.

Adolescent↗
PubMed1995

Induction of neuronal apoptosis by excitotoxins associated with long-lasting increase of 12-O-tetradecanoylphorbol 13-acetate-responsive element-binding activity.

We show that excitotoxic cell death, which is associated with pathological neurodegenerative processes, can display morphological and biochemical features characteristic of apoptosis, a mode of cell death typical of physiological neuronal elimination during development. Cortical neurons cultured in the absence of serum, stimulated with NMDA, glutamate, or quisqualate after 3-5 days in vitro, showed significant degeneration. This death was blocked by 1 microM MK-801, indicating that it was mediated by the activation of NMDA receptors. Dying cells displayed an apoptotic morphology, characterized by cytoplasm and chromatin condensation. No internucleosomal DNA degradation was observed, confirming that morphological changes of apoptosis can be dissociated from DNA laddering. Inhibitors of protein or RNA synthesis abolished cell death, and the protective effect of cycloheximide was similar when the drug was applied 2 h before or 8 h after glutamate. These experiments suggest the participation of active gene transcription in the mechanism of death. We thus analyzed the modulation of transcription factors in dying cells using electrophoretic mobility shift assays. The level of factors binding to the 12-O-tetradecanoylphorbol 13-acetate-responsive element (TRE) displayed a late and sustained increase preceding neuronal death, which was not found for factors complexing the Sp1 P, Oct, and USF binding sites. These results raise the possibility that apoptosis is one of the mechanisms of death in the pathologies linked to excitotoxicity and that activation of TRE-binding factors could play a role in these processes.

Animals↗
PubMed2001

Reelin' in Genes for Cortical Dysplasia.

Malformations of cortical development are a broad family of disorders that are characterized by abnormal cytoarchitecture of the cerebral cortex and a high association with epilepsy. In recent years positional cloning strategies have been implemented to identify several distinct gene mutations that are responsible for developmental brain malformations. The defined functional roles of proteins encoded by these genes have provided pivotal insights into the cellular mechanisms of brain development. Identification of these genes provides important clinical information used in genetic counseling for patients and their families.

Journal Article↗
PubMed2000

Epilepsy surgery in infancy.

Surgery for intractable epilepsy is being offered at progressively younger ages, including infancy. The most common causes of catastrophic epilepsy in very young surgical candidates are focal malformations of cortical development and low-grade tumors. Additional causes include Sturge-Weber syndrome, epidermal nevus syndrome, hemimegalencephaly, and prenatal or perinatal infarction. Many infants manifest with focal seizures, whereas some patients have infantile spasms in the setting of a focal epileptogenic lesion. Video electroencepholography, magnetic resonance imaging, and positron emission tomography are critical investigations to explore surgical options. In small series, the percentage of infants free of seizures after surgery was in the range of 60%. This is similar to that seen after epilepsy surgery in older children, adolescents, and adults. However, larger series with long-term follow up will be important. Furthermore, the extensive procedures required in infants for removal of the epileptogenic developmental lesions entail some risk, and should not be offered in the absence of severe epilepsy. Most infant candidates for epilepsy surgery have significant developmental delay. Few data are available, but anecdotal experience suggests that surgical relief of catastrophic epilepsy may result in resumption of developmental progression. For each infant, the timing of surgery must be carefully considered based on full assessment of the relative risks and benefits, derived from a detailed presurgical evaluation.

Brain↗
PubMed2000

Fat embolism syndrome after cementless total hip arthroplasty.

There are few reports in the literature of fat embolism syndrome after cementless total hip arthroplasty (THA). Most reported cases have occurred after fracture or cemented THA. We report a case of a healthy 51-year-old woman who underwent THA for osteoarthritis under spinal anesthesia. A press-fit cup and extensively porous-coated diaphyseal locking stem were used and inserted without cement. In the recovery room, the patient became hypoxemic and hypotensive and developed cortical blindness. The next day, a petechial rash was evident. Gurd's criteria for fat embolism syndrome were fulfilled. Her symptoms resolved over a 2-week period. Patients undergoing cementless THA are at risk for fat embolism syndrome, and this must be considered in the differential diagnosis for postoperative hypoxemia and neurologic deficits.

Arthroplasty, Replacement, Hip↗
PubMed2002

Neuroimaging of epilepsy.

Neuroimaging has an important role in the investigation and treatment of patients with epilepsy. Diagnosis of the underlying substrate in a given patient with epilepsy determines prognosis with higher accuracy than electroencephalography. Neuroimaging techniques include computed tomography (CT) and magnetic resonance imaging (MRI), although CT has a diminished role for diagnosis. MRI is the most appropriate imaging technique in the initial investigation of patients with epilepsy. MRI is the most sensitive technique for the diagnosis of hippocampal sclerosis, tumors, and malformations of cortical development. MRI is also critical for neurosurgical planning. Other imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography are reserved for patients with intractable epilepsy when surgery is contemplated. New developments such as MR spectroscopy, receptor PET, and magnetic source imaging are becoming clinical tools and have the promise of improving diagnosis.

Epilepsy↗
PubMed1998

Twins with different temporal lobe malformations: schizencephaly and arachnoid cyst.

The etiology and relationships between different forms of malformations of cortical development are poorly understood. Schizencephaly is generally regarded as unrelated to arachnoid cysts. As part of a systematic study of epilepsy in twins we observed a monozygotic twin pair discordant for temporal lobe epilepsy where the twin with epilepsy had unilateral temporal schizencephaly and periventricular heterotopia. The twin without epilepsy had an arachnoid cyst in the same temporal lobe. Although an incidental association is possible, this observation, together with occasional reports of schizencephaly and arachnoid cysts within one individual, suggests a shared pathogenic mechanism. Schizencephaly can be caused by both genetic and acquired factors. We propose that our observations in this twin pair are best explained by a genetic factor present in both twins, with an additional environmental insult resulting in schizencephaly in only one of the pair.

Adult↗
PubMed1994

Prefertilization gamete maturation events in marsupials.

Despite many fundamental similarities between the gametes of marsupials and placental mammals, the regulation and timing of prefertilization gamete maturation are quite different. The marsupial acrosome is remarkably stable and an acrosome reaction (AR) is not induced by reagent effective for the sperm of placental mammals. The ultrastructure of the marsupial sperm AR is essentially similar to that of placental mammals, however, whether an equatorial segment (ES) persists to serve as the site of sperm-egg membrane fusion is unclear. Diacylglycerol induction of the AR suggests that the sperm of Australian species lack an ES, yet an ES-like region appears to be involved in fertilization in the opossum Monodelphis. The marsupial oocyte, unlike those of placentals, continues to grow throughout follicular life and major cytoplasmic maturation events occur late in oocyte development. Cortical granules only become evident shortly before ovulation and mature dark granules may only appear after ovulation. Further, the zona pellucida (ZP) changes in character and function during the peri-ovulatory period. In vitro fertilization has been achieved for an opossum but not for any Australian marsupial, owing to failure of sperm-ZP binding. Requirement for a sperm maturation process is likely, but capacitation treatments used for placental sperm in vitro have been ineffective. Since it is now feasible to experimentally manipulate marsupial gametes in vitro major advances in our understanding of their function can be expected.

Acrosome↗
PubMed1990

Endogenous neurotransmitter activates N-methyl-D-aspartate receptors on differentiating neurons in embryonic cortex.

Before synapses form in embryonic turtle cerebral cortex, an endogenous neurotransmitter activates N-methyl-D-aspartate (NMDA) channels on neurons in the cortical plate. Throughout cortical development, these channels exhibit voltage-dependent Mg2+ blockade and are antagonized by D-2-amino-5-phosphonovaleric acid, a selective NMDA receptor antagonist. The activation in situ of these nonsynaptic NMDA channels demonstrates a potential physiological substrate for control of early neuronal differentiation.

2-Amino-5-phosphonovalerate↗
PubMed1992

Detection of dystrophin in the postsynaptic density of rat brain and deficiency in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a common, lethal, chromosome X-linked inherited disease. Moderate cognitive impairment is a feature of DMD, but the underlying mechanisms are unknown. DMD is characterized by a defect in a protein, dystrophin, that is located predominantly in muscle but has been detected in brain. We sought to directly localize dystrophin within the complex synaptic structure of the cerebral cortex by focusing on the postsynaptic density (PSD), which appears to be central to synaptic function. We report that a specific anti-dystrophin antibody (anti 6-10) recognizes three distinct proteins in the purified PSD: the 400-kDa dystrophin and two previously unidentified dystrophin-related proteins of 120 and 110 kDa. These proteins exhibited differential regional expression in PSDs from cerebral cortex, cerebellum, and olfactory bulb. In the cortical PSD, the 400-kDa dystrophin was predominant, whereas the 120-kDa protein was the major species in cerebellum and olfactory bulb PSDs. The three proteins were differentially expressed in the PSD during cortical development: the 400-kDa protein exhibited a selective 9-fold increase during postnatal days 7 to 10, suggesting a normal physiological role in synaptic maturation. The PSD from the mdx mouse, a model of human DMD, contained no detectable 400-kDa dystrophin but expressed the two dystrophin-related proteins. Our results indicate that brain dystrophins are localized to the PSD, potentially as three isoforms, and raise the possibility that cognitive abnormalities in DMD are attributable to synaptic dysfunction associated with deficits in brain dystrophin molecules.

Animals↗
PubMed2001

Identification of genes induced in peripheral nerve after injury. Expression profiling and novel gene discovery.

Peripheral nerve injury results in axonal degeneration and in phenotypic changes of the surrounding Schwann cells, whose presence is critical for nerve regeneration. To identify genes induced after nerve injury in Schwann cells, we developed a strategy that included differential screening of a subtractive library enriched for cDNAs expressed in injured nerve, sequence analysis, and expression profiling. By using real time quantitative reverse transcriptase-polymerase chain reaction, we found that injury-induced genes could be categorized into four temporal expression patterns. Among the clones we identified were a number that were homologous only to expressed sequence tags in the data base. These were stratified based on their expression profile, presence of identifiable sequence motifs, homologies to other proteins, and evolutionary conservation. We chose one representative gene, nin283, to analyze in detail. The nin283 gene encodes a 227-residue protein containing both a zinc finger and a RING finger motif. nin283 is highly expressed in the central nervous system, particularly in the developing cortical plate in embryos. It is also expressed in peripheral ganglia and is induced by nerve growth factor in PC12 cells. Subcellular localization analysis demonstrated that Nin283 is located in the endosome/lysosome compartment, suggesting that it may participate in ubiquitin-mediated protein modification.

Amino Acid Motifs↗
PubMed2003

Close homolog of L1 is an enhancer of integrin-mediated cell migration.

Close homolog of L1 (CHL1) is a member of the L1 family of cell adhesion molecules expressed by subpopulations of neurons and glia in the central and peripheral nervous system. It promotes neurite outgrowth and neuronal survival in vitro. This study describes a novel function for CHL1 in potentiating integrin-dependent cell migration toward extracellular matrix proteins. Expression of CHL1 in HEK293 cells stimulated their haptotactic migration toward collagen I, fibronectin, laminin, and vitronectin substrates in Transwell assays. CHL1-potentiated cell migration to collagen I was dependent on alpha1beta1 and alpha2beta1 integrins, as shown with function blocking antibodies. Potentiated migration relied on the early integrin signaling intermediates c-Src, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase. Enhancement of migration was disrupted by mutation of a potential integrin interaction motif Asp-Gly-Glu-Ala (DGEA) in the sixth immunoglobulin domain of CHL1, suggesting that CHL1 functionally interacts with beta1 integrins through this domain. CHL1 was shown to associate with beta1 integrins on the cell surface by antibody-induced co-capping. Through a cytoplasmic domain sequence containing a conserved tyrosine residue (Phe-Ile-Gly-Ala-Tyr), CHL1 recruited the actin cytoskeletal adapter protein ankyrin to the plasma membrane, and this sequence was necessary for promoting integrin-dependent migration to extracellular matrix proteins. These results support a role for CHL1 in integrin-dependent cell migration that may be physiologically important in regulating cell migration in nerve regeneration and cortical development.

Cell Adhesion Molecules↗
PubMed2005

Ocimum sanctum modulates selenite-induced cataractogenic changes and prevents rat lens opacification.

PURPOSE: To study the effect of Ocimum sanctum (OS) on selenite-induced morphological and biochemical changes in isolated rat lenses as well as on cataract incidence in rat pups. METHODS: Transparent rat lenses were divided into normal, selenite-only, and four treated groups. Selenite-only and treated group lenses were subjected to oxidative stress in vitro by incorporating sodium selenite (100 microM) in the culture medium. The effect of OS (70, 140, 280, and 560 microg/ml) was studied on the levels of reduced glutathione (GSH) and thiobarbituric acid reacting substances (TBARS) in selenite-challenged lenses. The lowest concentration of OS offering significant modulation on these two parameters was determined. Subsequently, the effect of prior and cotreatment with the lowest effective concentration of OS was studied on TBARS, GSH, and on lens antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSHPx), catalase (CAT), and glutathione-S-transferase (GST). Changes in lens protein profiles under different incubation conditions were analyzed by SDS gel-electrophoresis. In vivo, cataract was induced by a single subcutaneous injection of sodium selenite (25 micromole/kg b.w.) to 9-day-old rat pups. The anticataract effect of OS (5 and 10 mg/kg b.w.) injected intraperitoneally 4 hr prior to selenite challenge was evaluated by the presence of lens nuclear opacity in rat pups on the 16th postnatal day. Insolubilization of lens proteins post-selenite injection was monitored for 4 days. RESULTS: The lenses in the selenite-only group developed cortical opacities in 24 hr. OS showed different degrees of positive modulation in selenite-induced morphological as well as biochemical changes. The lowest effective dose of OS that significantly modulated glutathione and thiobarbituric acid reacting substances was found to be 140 microg/ml. At this dose, a significant increase in antioxidant enzyme levels and preservation of normal lens protein profile was observed. OS at the dose of 70 microg/ml did not show any significant protection with respect to either morphology or biochemistry of lenses. In vivo, 5 and 10 mg/kg of OS reduced the incidence of selenite cataract by 20% and 60%, respectively, and prevented protein insolubilization as well. CONCLUSIONS: Aqueous extract of OS possesses potential anticataract activity against selenite-induced experimental cataractogenesis. The protective effect was supported by restoration of the antioxidant defense system and inhibition of protein insolubilization of rat lenses as well.

Animals↗
PubMed2003

The left human speech-processing cortex is thinner but longer than the right.

We present histological data from 21 post-mortem, adult human cases that indicate the neocortex on the left planum temporale (secondary auditory cortex) is thinner but longer than that on the right side. The volumes of the left and right regions are approximately equal. Thus, the left planum temporale cortex is long and thin and the right short and thick. The present data fit excellently with previous studies of the volume, surface area, cytoarchitectonics, and neuronal structures of these areas. From these studies we suggest that the hemispheric differences arise from a so-called "balloon model" of cortical development. In this the cortex is extended and stretched by white matter growth. The stretching is greater on the left side, leaving greater distances between neuronal columns and more tangentially (to the pial surface) oriented dendrites on that side. This difference in fine structure can result in more independent activity of individual columns on the left, and could be an anatomical factor in the usual dominance of the left hemisphere for speech perception (Seldon, 1982, 1985).

Journal Article↗
PubMed2002

A locus for bilateral perisylvian polymicrogyria maps to Xq28.

Polymicrogyria (PMG) is one of a large group of human cortical malformations that collectively account for a significant percentage of patients with epilepsy, congenital neurological deficits, and intellectual disability. PMG is characterized by an excess of small gyri and abnormal cortical lamination. The most common distribution is bilateral, symmetrical, and maximal, in the region surrounding the sylvian fissures, and is known as "bilateral perisylvian polymicrogyria" (BPP). Most cases are sporadic, although several families have been observed with multiple affected members, usually following an X-linked inheritance pattern. Here we report the first genetic locus for BPP mapped by linkage analysis in five families. Linkage places the critical region for BPP at Xq28 (LOD score 3.08 in Xq28, distal to DXS8103 by multipoint analysis). We suggest that this region contains a gene that is necessary for correct neuronal organization and that the identification of this gene will both enhance our understanding of normal cortical development and accelerate the identification of other genes responsible for PMG.

Cerebral Cortex↗