Interrelationship of Genetics and Prenatal Injury in the Genesis of Malformations of Cortical Development

Montenegro, Maria Augusta; Guerreiro, Marilisa M.; Lopes-Cendes, Íscia; Guerreiro, Carlos A. M.; Cendes, Fernando

doi:10.1001/archneur.59.7.1147

Cited by 67 publications

(55 citation statements)

References 32 publications

(55 reference statements)

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“…Although the exact pathogenesis of MCD remains unknown, environmental factors also appear to be involved (Montenegro et al, 2002;Montenegro, 2003;Bassanini and Battaglia, 2006).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

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Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

et al. 2006

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Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. MCD are believed to be the morphological and perhaps physiological bases of several neurological diseases, spanning from mental retardation to autism and epilepsy. In view of the fact that during development, an appropriate blood supply is necessary to drive organogenesis in other organs, we hypothesized that vasculogenesis plays an important role in brain development and that E15 exposure in rats to the angiogenesis inhibitor thalidomide would cause postnatal MCD. Our results demonstrate that thalidomide inhibits angiogenesis in vitro at concentrations that result in significant morphological alterations in cortical and hippocampal regions of rats prenatally exposed to this vasculotoxin. Abnormal neuronal development was associated with vascular malformations and a leaky blood-brain barrier. Protein extravasation and uptake of fluorescent albumin by neurons, but not glia, was commonly associated with abnormal cortical development. Neuronal hyperexcitability was also a hallmark of these abnormal cortical regions. Our results suggest that prenatal vasculogenesis is required to support normal neuronal migration and maturation. Altering this process leads to failure of normal cerebrovascular development and may have a profound implication for CNS maturation.Keywords cortical dysplasia; angiogenesis; brain development; vasculogenesis; blood-brain barrier; endothelium Malformations of cortical development (MCD) result from abnormal neuronal positioning during corticogenesis. Genetic/epigenetically-induced MCD represent one of the most common etiologic factors associated with CNS pathologies, i.e. neurological deficits, autism, developmental delay, and epilepsy (Taylor et al., 1971;Robain, 1996). While the exact mechanisms underlying MCD are unknown, it is clear that single genes may be responsible for distinct MCD including lissencephaly, subcortical band heterotopias, NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2014 January 23. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript periventricular nodular heterotopia, and tuberous sclerosis (Gardiner, 1999;Steinlein, 2004). Although the exact pathogenesis of MCD remains unknown, environmental factors also appear to be involved (Montenegro et al., 2002;Montenegro, 2003;Bassanini and Battaglia, 2006).Animal models of CNS disorders have provided a crucial step toward both the understanding of mechanisms involved and discovery of therapeutic factors. In the case of MCD, the animal model that most realistically recapitulates the morphology of human cortical dysplasia is based on prenatal exposure to methylazoxymethanol acetate (MAM; Battaglia et al., 2003a). A prenatal exposure to this putative anti-proliferative and cytotoxic agent (Cattaneo et al., 1995) induces cerebral heterotopias that share striking similarities with those observed in humans (Colacitti et al., 1999;Battaglia et al., 2003a)...

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“…Although the exact pathogenesis of MCD remains unknown, environmental factors also appear to be involved (Montenegro et al, 2002;Montenegro, 2003;Bassanini and Battaglia, 2006).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Although the exact pathogenesis of MCD remains unknown, environmental factors also appear to be involved (Montenegro et al, 2002;Montenegro, 2003;Bassanini and Battaglia, 2006). Animal models of CNS disorders have provided a crucial step toward both the understanding of mechanisms involved and discovery of therapeutic factors.…”

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Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

et al. 2006

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“…There have been tremendous advances in understanding the basis of normal and abnormal cortical development by studying genetic causes of MCD (Olson and Walsh, 2002). However, the most common cases of MCD presenting in humans, especially focal cortical dysplasia (usually in young adults presenting to epilepsy centers), are sporadic and thought to be attributable to an interplay of environmental and genetic factors (Montenegro et al, 2002;Sisodiya, 2004). Although it is now clear that the marginal zone and Cajal-Retzius cells are key players in cortical development, there is little understanding of why it becomes so disorganized in a variety of MCD.…”

Section: Introductionmentioning

confidence: 99%

Stromal-Derived Factor-1 (CXCL12) Regulates Laminar Position of Cajal-Retzius Cells in Normal and Dysplastic Brains

Paredes

Li²,

Berger³

et al. 2006

J. Neurosci.

118

109

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Normal brain development requires a series of highly complex and interrelated steps. This process presents many opportunities for errors to occur, which could result in developmental defects in the brain, clinically referred to as malformations of cortical development. The marginal zone and Cajal-Retzius cells are key players in cortical development and are established early, yet there is little understanding of the factors resulting in the disruption of the marginal zone in many types of cortical malformation syndromes. We showed previously that treatment with methylazoxymethanol in rats causes marginal zone dysplasia with displacement of Cajal-Retzius cells to deeper cortical layers. Here we establish that loss of activity of the chemokine stromal-derived factor-1 (SDF1) (CXCL12), which is expressed by the leptomeninges, is necessary and sufficient to cause marginal zone disorganization in this widely used teratogenic animal model. We also found that mice with mutations in the main receptor for SDF1 (CXCR4) have Cajal-Retzius cells displaced to deeper cortical layers. Furthermore, by inhibiting SDF1 signaling in utero by intraventricular injection of a receptor antagonist, we establish that SDF1 signaling is required for the maintenance of Cajal-Retzius cell position in the marginal zone during normal cortical development. Our data imply that cortical layering is not a static process, but rather requires input from locally produced molecular cues for maintenance, and that complex syndromes of cortical malformation as a result of environmental insults may still be amenable to explanation by interruption of specific molecular signaling pathways.

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“…A series of 76 consecutive patients with MCD and their families were systematically questioned about their family histories of epilepsy or other neurological impairment and the occurrence of prenatal events 31 . Our findings supported the idea of a spectrum of different types of MCD.…”

Section: And Epilepsymentioning

confidence: 99%

“…This entity is the mildest extreme of a broad clinical spectrum of the perisylvian syndrome. Epilepsy is present in less than half of the patients and, when present, is easily controlled with antiepileptic drugs 31,32 . Refractory epilepsy is rarely found in patients with PMG.…”

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confidence: 99%

Malformations of cortical development

Guerreiro

2009

Arq. Neuro-Psiquiatr.

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-Malformations of cortical development (MCD) have been increasingly identified. The purpose of this presentation is to review the current knowledge of the MCD. Before we address this issue, we will briefly present a review of cortical development. The second part of this presentation will address the most important MCD. Finally, the last part of this presentation will address the correlation between MCD and epilepsy.KEY WORDS: malformations of cortical development, focal cortical dysplasias, neuronal migration disorders, cortical organization disorders. Malformações do desenvolvimento corticalResumo -As malformações do desenvolvimento cortical (MDC) são cada vez mais identificadas e diagnosticadas. O propósito desta apresentação é rever o conhecimento recente sobre as MDC. Antes de abordarmos o assunto em questão, apresentaremos brevemente uma revisão sobre a formação cortical. A seguir, abordaremos as principais entidades compreendidas dentro da classificação das MDC e, finalmente, resumiremos a correlação entre MDC e epilepsia.PALAVRAS-CHAVE: malformações do desenvolvimento cortical, displasias corticais focais, distúrbios da migração neuronal, distúrbios da organização cortical. Malformations of cortical development (MCD) have been increasingly identified as a major cause of several disorders, particularly in childhood. Patients with MCD present with a wide spectrum of clinical manifestations ranging from asymptomatic cases to those with epilepsy and neurodevelopmental problems. The advent of the magnetic resonance imaging (MRI) has been the most important factor in the improvement of the diagnosis, which has allowed a better clinical management. Structural imaging has become more sensitive with developments of MRI hardware, acquisition and postprocessing methods.The purpose of this presentation is to review the current knowledge of MCD. Before we address this issue, we will briefly present a review of cortical development. The second part of this presentation will address the most important MCD. Finally, the last part of this presentation will address the correlation between MCD and epilepsy. Barkovich et al. 1 proposed a classification of the malformations of cortical development, taking into account pathological, genetic and neuroimaging features of the different stages of development. They state that there are three main consecutive stages of cortical development, each of them partially overlapping with the previous stage. They are: cellular proliferation and differentiation, neuronal migration, and cortical organization. CORTICAL DEVELOPMENTThe first step of cortical development is cellular proliferation and differentiation, which takes place between the 5 th week and 20 th week of gestation. The germinal or primordial cell multiplies and differentiates becoming either a neuron or glial cell. A general rule of the developing nervous system is that a cell is generated in a different location from its final position in the central nervous system (CNS). The process of changing position from birth ...

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Interrelationship of Genetics and Prenatal Injury in the Genesis of Malformations of Cortical Development

Cited by 67 publications

References 32 publications

Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations

Stromal-Derived Factor-1 (CXCL12) Regulates Laminar Position of Cajal-Retzius Cells in Normal and Dysplastic Brains

Malformations of cortical development

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