Cerebral Cortical Development Research Articles

Enhanced expression of Pafah1b1 causes over-migration of cerebral cortical neurons into the marginal zone.

Mutations of PAFAH1B1 cause classical lissencephaly in humans. In addition, duplications and triplications of PAFAH1B1 are found in individuals with intellectual disability and other neurological disorders suggesting that proper brain development is highly sensitive to the PAFAH1B1 dosage. To examine the effect of PAFAH1B1 over-dosage in neural development, especially in migration of neurons and layer formation during cerebral cortical development, we overexpressed Pafah1b1 in migrating neurons in the mouse embryonic cortex using in utero electroporation. Enhanced expression of Pafah1b1 in radially-migrating neurons resulted in their over-migration into the marginal zone. Neurons that invaded the marginal zone were oriented abnormally. Layer distribution of Pafaha1b1-overexpressing neurons shifted more superficially than control neurons. Some of the Pafaha1b1-overexpressing future layer 4 neurons changed their positions to layers 2/3. Furthermore, they also changed their layer marker expression from layer 4 to layers 2/3. These results suggest that overexpression of Pafah1b1 affects the migration of neurons and disrupts layer formation in the developing cerebral cortex, and further support the idea that appropriate dosage of Pafah1b1 is crucial for the proper development of the brain.

APC sets the Wnt tone necessary for cerebral cortical progenitor development.

Adenomatous polyposis coli (APC) regulates the activity of β-catenin, an integral component of Wnt signaling. However, the selective role of the APC-β-catenin pathway in cerebral cortical development is unknown. Here we genetically dissected the relative contributions of APC-regulated β-catenin signaling in cortical progenitor development, a necessary early step in cerebral cortical formation. Radial progenitor-specific inactivation of the APC-β-catenin pathway indicates that the maintenance of appropriate β-catenin-mediated Wnt tone is necessary for the orderly differentiation of cortical progenitors and the resultant formation of the cerebral cortex. APC deletion deregulates β-catenin, leads to high Wnt tone, and disrupts Notch1 signaling and primary cilium maintenance necessary for radial progenitor functions. β-Catenin deregulation directly disrupts cilium maintenance and signaling via Tulp3, essential for intraflagellar transport of ciliary signaling receptors. Surprisingly, deletion of β-catenin or inhibition of β-catenin activity in APC-null progenitors rescues the APC-null phenotype. These results reveal that APC-regulated β-catenin activity in cortical progenitors sets the appropriate Wnt tone necessary for normal cerebral cortical development.

The prenatal ultrasonic study of cerebral sulci and gyrus development in fetuses with conotruncal defects at the second and third trimester

Objective To evaluate the development of cerebral sulci and gyrus in fetuses with conotruncal defect(CTD) at the second and third trimester by ultrasound, and to improve clinician′s understanding of the cerebral cortical development in fetuses with CTD. Methods The study was conducted at Shenzhen Maternity and Child Healthcare Hospital Affiliated to Southern Medicial University from December 2015 to January 2017, enrolled 180 women with single fetus, among whom 60 fetuses with CTD and gestational age between 20 weeks to 33+ 6 weeks were diagnosed by echocardiographic examination. CTD included persistent truncus arteriosous, tetralogy of fallot, transpofition of the great arteries and double outlet of right ventricle. Evaluation indexes of cerebral sulci and gyrus included depth and angle of parietooccipital sulcus, width and depth of sylvian fissure, uncovered width of insular, uncovered insular ratio, depth of calcarine sulcus, head circumference; evaluation indexes of hemodynamics included umbilical artery resistance index, umbilical artery pulsation index, middle cerebral artery resistance index, middle cerebral artery pulsation index, the cerebral-to-placental resistance ratio and the cerebroplacental pulsation ratio. Above indexes were measured for statistical analysis. Results At the whole gestational age in the study, depth of parietooccipital sulcus and width of sylvian fissure in CTD fetuses were smaller than those in the control group, uncovered insular ratio was larger than that in the normal group(P<0.05); middle cerebral artery resistance index, middle cerebral artery pulsation index and the cerebroplacental pulsation ratio in CTD fetuses were lower than those of the control group (P<0.05). Conclusions The change of hemodynamics in fetuses with CTD may be one of the reasons that fetuses with CTD have cerebral cortical hypoevolutism. Key words: Ultrasonography, prenatal; Fetus; Conotruncal defects; Sulci and gyrus

Afadin controls cell polarization and mitotic spindle orientation in developing cortical radial glia

BackgroundIn developing tissues, cell polarity and tissue architecture play essential roles in the regulation of proliferation and differentiation. During cerebral cortical development, adherens junctions link highly polarized radial glial cells in a neurogenic niche that controls their behavior. How adherens junctions regulate radial glial cell polarity and/or differentiation in mammalian cortical development is poorly understood.ResultsConditional deletion of Afadin, a protein required for formation and maintenance of epithelial tissues, leads to abnormalities in radial glial cell polarity and subsequent loss of adherens junctions. We observed increased numbers of obliquely-oriented progenitor cell divisions, increased exit from the ventricular zone neuroepithelium, and increased production of intermediate progenitors.ConclusionsTogether, these findings indicate that Afadin plays an essential role in regulating apical-basal polarity and adherens junction integrity of radial glial cells, and suggest that epithelial architecture plays an important role in radial glial identity by regulating mitotic orientation and preventing premature exit from the neurogenic niche.

Psychosis and Schizencephaly – A case report and systematic review

Psychotic symptoms have been reported in association with a wide array of brain abnormalities. Few published reports have examined the association between schizencephaly and psychiatric illness. Originally defined by Wilmarth and later by Yakolev and Wadsworth – Schizencephaly is an uncommon congenital disorder of cerebral cortical development, defined as a grey matter-lined cleft extending from the pial surface to the ventricle. The nosology is based on neuroradiologic findings and confirmed by neuropathology when available. The Clinical presentation and neurodevelopmental outcomes of the disorder vary and are usually related to the extent/areas of the brain involved. In this article we review the medical literature around Schizencephaly paying particular attention to the pathophysiology, etiology and diagnosis of such patients. We then present a case of Schizencephaly and first episode psychosis in a 16-year-old adolescent who was admitted to our inpatient psychiatric service. Lastly, we present the findings of a systematic review from PubMed whereby we summarize 10 cases of Schizencephaly with associated psychiatric symptoms.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The progress of imaging in the study of cerebral cortical development in fetuses and neonates with congenital heart disease

The progress of imaging in the study of cerebral cortical development in fetuses and neonates with congenital heart disease

Combined allelic dosage of Nfia and Nfib regulates cortical development.

Background:Nuclear factor I family members nuclear factor I A and nuclear factor I B play important roles during cerebral cortical development. Nuclear factor I A and nuclear factor I B regulate similar biological processes, as their expression patterns, regulation of target genes and individual knockout phenotypes overlap. We hypothesised that the combined allelic loss of Nfia and Nfib would culminate in more severe defects in the cerebral cortex than loss of a single member.Methods:We combined immunofluorescence, co-immunoprecipitation, gene expression analysis and immunohistochemistry on knockout mouse models to investigate whether nuclear factor I A and nuclear factor I B function similarly and whether increasing allelic loss of Nfia and Nfib caused a more severe phenotype.Results:We determined that the biological functions of nuclear factor I A and nuclear factor I B overlap during early cortical development. These proteins are co-expressed and can form heterodimers in vivo. Differentially regulated genes that are shared between Nfia and Nfib knockout mice are highly enriched for nuclear factor I binding sites in their promoters and are associated with neurodevelopment. We found that compound heterozygous deletion of both genes resulted in a cortical phenotype similar to that of single homozygous Nfia or Nfib knockout embryos. This was characterised by retention of the interhemispheric fissure, dysgenesis of the corpus callosum and a malformed dentate gyrus. Double homozygous knockout of Nfia and Nfib resulted in a more severe phenotype, with increased ventricular enlargement and decreased numbers of differentiated glia and neurons.Conclusion:In the developing cerebral cortex, nuclear factor I A and nuclear factor I B share similar biological functions and function additively, as the combined allelic loss of these genes directly correlates with the severity of the developmental brain phenotype.

APC sets the Wnt tone necessary for cerebral cortical progenitor development

APC sets the Wnt tone necessary for cerebral cortical progenitor development

A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A.

BackgroundMicrotubules are dynamic polymers of α/β tubulin heterodimers that play a critical role in cerebral cortical development, by regulating neuronal migration, differentiation, and morphogenesis. Mutations in genes that encode either α‐ or β‐tubulin or a spectrum of proteins involved in the regulation of microtubule dynamics lead to clinically devastating malformations of cortical development, including lissencephaly.MethodsThis is a single case report or a patient with lissencephaly, developmental delay, nystagmus, persistent hyperplastic primary vitreous, and infantile spasms, and undertook a neurogenetic workup. We include studies of mutant function in Escherichia coli and HeLa cells.ResultsThe patient was found to have a novel de novo mutation in kinesin family member 2A (KIF2A). This mutation results in a substitution of isoleucine at a highly conserved threonine residue within the ATP‐binding domain. The KIF2A p.Thr320Ile mutant protein exhibited abnormal solubility, and KIF2A p.Thr320Ile overexpression in cultured cells led to the formation of aberrant microtubule networks.ConclusionFindings support the pathogenic link between KIF2A mutation and lissencephaly, and expand the range of presentation to include infantile spasms and congenital anomalies.

Role of Magnetic Resonance Imaging in the Diagnosis of Fetal Brain Anomalies

ABSTRACT Prenatal Ultrasonagraphy (US) is the mainstay modality to diagnose fetal abnormalities especially in early pregnancy. Fetal Magnetic Resonance Imaging (MRI) is a useful tool to confirm and to characterize a pathology that is suspected on US, especially in the detection of central nervous system pathologies. The use of ultrafast imaging tecniques gives additional importantant informations and optimal imaging quality, despite fetal motion, in clinical practice. Diffusion Weighted Imaging (DWI), Diffusion Tensor Imaging (DTI), MR Spetroscopy and Functional studies have potential applications in the fetal brain imaging. Fetal MRI could recognize, in contradistinction to US, the development of fetal brain, the multilayered appearance of the cerebral parenchyma, the timing of sulci development and the myelination. The most common indications for fetal MRI are ventriculomegaly, midline anomalies, malformations of cerebral cortical development, posterior fossa anomalies, suspected haemorraghic-ischemic lesions, tumors. Fetal MRI is a safe and powerful complement to US for clinical management and prognostication. How to cite this article Resta M, Dicuonzo F, Resta M. Role of Magnetic Resonance Imaging in the Diagnosis of Fetal Brain Anomalies. Donald School J Ultrasound Obstet Gynecol 2017;11(4):328-340.

Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds ofdifferentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

Editorial: In vivo Cell Biology of Cerebral Cortical Development and Its Related Neurological Disorders.

The brain consists of complex but precisely organized neural networks, which determine the structural basis of higher order functions. Remarkably, this complex structure originates from a simple pseudostratified neuroepithelium. How it is formed is best seen in the elegant example of the cerebral cortex. In the developing mammalian cerebral cortex, polarized neural progenitors are arranged in a pseudostratified structure that forms the mitotically active ventricular zone. At the onset of neurogenesis, a cohort of neural progenitors differentiates into neurons and through multi-step modes of migration generates a six-layered structured cerebral cortex. Defects in neurogenesis and neuronal migration can cause several neurological disorders, including microcephaly and lissencephaly. Importantly, recent advances in not only human and mouse genetic approaches but also the use of a number of novel techniques, particularly in vivo electroporation and time-lapse analyses of explant slice culture, have significantly increased our understanding of cortical development. In addition, these novel techniques have allowed us to open a new avenue for cell biological analyses of cortical development in vivo or ex vivo.

Schizencephaly and psychosis: A case report

IntroductionSchizencephaly is a rare malformation of the central nervous system, a congenital disorder of cerebral cortical development resulting in the formation of abnormal unilateral or bilateral clefts in the cerebral hemispheres that extends from the pial surface to the ventricle. It often manifests with partial seizures, mental retardation and hemiparesis.ObjectiveTo illustrate a rare case of association between psychosis and schizencephaly and the implication of this association for understanding the biology of the psychosis.MethodsA literature search was performed on PubMed database using the key words schizencephaly, psychosis, brain diseases and retrieved papers were selected according to their relevance. The patient clinical record was reviewed.ResultsThe authors report a case of a 59-year-old male admitted into a psychiatric hospital with insomnia, disorganized behavior probably secondary to auditory hallucinations and mystic delusions. He also reported epilepsy and strabismus in his right eye since his childhood and right facial paresis. A head CT scan revealed a left deep cortico-ventricular parieto-occipital communication corresponding to schizencephaly.ConclusionsConsidering the theory that schizophrenia is associated with abnormal brain development, this case report may provide an example of a neurodevelopment abnormality that manifests as psychosis.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Compensatory Actions of Ldb Adaptor Proteins During Corticospinal Motor Neuron Differentiation.

Although many genes that specify neocortical projection neuron subtypes have been identified, the downstream effectors that control differentiation of those subtypes remain largely unknown. Here, we demonstrate that the LIM domain-binding proteins Ldb1 and Ldb2 exhibit dynamic and inversely correlated expression patterns during cerebral cortical development. Ldb1-deficient brains display severe defects in proliferation and changes in regionalization, phenotypes resembling those of Lhx mutants. Ldb2-deficient brains, on the other hand, exhibit striking phenotypes affecting layer 5 pyramidal neurons: Immature neurons have an impaired capacity to segregate into mature callosal and subcerebral projection neurons. The analysis of Ldb2 single-mutant mice reveals a compensatory role of Ldb1 for Ldb2 during corticospinal motor neuron (CSMN) differentiation. Animals lacking both Ldb1 and Ldb2 uncover the requirement for Ldb2 during CSMN differentiation, manifested as incomplete CSMN differentiation, and ultimately leading to a failure of the corticospinal tract.

Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development.

Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis.

Cellullar insights into cerebral cortical development: focusing on the locomotion mode of neuronal migration.

The mammalian brain consists of numerous compartments that are closely connected with each other via neural networks, comprising the basis of higher order brain functions. The highly specialized structure originates from simple pseudostratified neuroepithelium-derived neural progenitors located near the ventricle. A long journey by neurons from the ventricular side is essential for the formation of a sophisticated brain structure, including a mammalian-specific six-layered cerebral cortex. Neuronal migration consists of several contiguous steps, but the locomotion mode comprises a large part of the migration. The locomoting neurons exhibit unique features; a radial glial fiber-dependent migration requiring the endocytic recycling of N-cadherin and a neuron-specific migration mode with dilation/swelling formation that requires the actin and microtubule organization possibly regulated by cyclin-dependent kinase 5 (Cdk5), Dcx, p27kip1, Rac1, and POSH. Here I will introduce the roles of various cellular events, such as cytoskeletal organization, cell adhesion, and membrane trafficking, in the regulation of the neuronal migration, with particular focus on the locomotion mode.

Epilepsy secondary to schizencephaly: A comparative study

Schizencephaly is an uncommon structural disorder of cerebral cortical development. There are few comparative studies evaluating epilepsy in that condition. The aim of this study is to analyze which factors are associated with the development of epilepsy in patients with schizencephaly. The study is a longitudinal, observational and comparative retrospective study of 35 pediatric patients with schizencephaly. The patients were divided into two groups: a group of 10 children who developed epilepsy and another group of 25 who had no clinical epileptic manifestations. Both groups were followed up and the data collected to analyze potential risk factors included demographic and prenatal data (prenatal event, family history of epilepsy), radiological features (location of the cleft, unilateral or bilateral, extent of the lesion, number of impaired lobes, open-lip or closed-lip types, presence of associated anomalies), and neurological and electroencephalographic data. No significant difference was found in the association between epilepsy and any of the examined factors (<i>P</i> > 0.05). Neither the features of the lesion (cleft size location, type of lip, number of impaired lobes, associated anomalies), nor electroencephalography abnormalities, nor the family history of epilepsy or prenatal events could predict the occurrence of epilepsy in patients with schizencephaly.

Focal Cortical Dysplasia.

Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly.

Emerging roles of Axin in cerebral cortical development.

Proper functioning of the cerebral cortex depends on the appropriate production and positioning of neurons, establishment of axon–dendrite polarity, and formation of proper neuronal connectivity. Deficits in any of these processes greatly impair neural functions and are associated with various human neurodevelopmental disorders including microcephaly, cortical heterotopias, and autism. The application of in vivo manipulation techniques such as in utero electroporation has resulted in significant advances in our understanding of the cellular and molecular mechanisms that underlie neural development in vivo. Axin is a scaffold protein that regulates neuronal differentiation and morphogenesis in vitro. Recent studies provide novel insights into the emerging roles of Axin in gene expression and cytoskeletal regulation during neurogenesis, neuronal polarization, and axon formation. This review summarizes current knowledge on Axin as a key molecular controller of cerebral cortical development.

PAK1 regulates cortical development via promoting neuronal migration and progenitor cell proliferation.

Backgroundp21-activated kinase 1 (PAK1) is a serine/threonine kinase known to be activated by the Rho family small GTPases and to play a key role in cytoskeletal reorganization, spine morphology and synaptic plasticity. PAK1 is also implicated in a number of neurodevelopmental and neurodegenerative diseases, including autism, intellectual disability and Alzheimer’s disease. However, the role of PAK1 in early brain development remains unknown.ResultsIn this study, we employed genetic manipulations to investigate the role of PAK1 in the cerebral cortical development in mice. We showed that compared to the wild type littermates, PAK1 knockout mice have a reduction in the number of pyramidal neurons in several layers of the cerebral cortex, which is associated with a smaller pool of neural progenitor cells and impaired neuronal migration.ConclusionThese results suggest that PAK1 regulates cortical development by promoting the proliferation of neural progenitor cells and facilitating the migration of these neurons to specific regions of the cortex.