Figure 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
MRI schemas of malformations. (A) Control brain, (B) Cobblestone lissencephaly, where neuronal overmigration (represented by gray patches at the surface of the brain) can arise due to breaks of the basement membrane. (C) Periventricular nodular heterotopia, some neurons (represented by gray nodules) remain stuck at the ventricular surface, most probably due to breaks and disorganization of the ventricular lining. (D) Microcephaly, several mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. In pure forms, brain architecture is relatively well-preserved, in other forms (microcephaly with simplified gyral pattern, MSGP, not shown), brain organization and cortical folds are also affected. (E) Globular or ribbon-like heterotopia, represented by gray globular masses. In this case the heterotopia starts at the level of the ventricles and fills up the white matter in some brain areas. The heterotopia can appear to have gyri. Modified from Francis et al. (2006).
Source publication
In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristi...
Contexts in source publication
Context 1
... malformations (Figure 1) are usually detected during pregnancy (fetal ultrasound), and are obvious after birth due to developmental delay, epilepsy and intellectual deficits. In human, magnetic resonance imaging (MRI) is used to classify the defects and if a genetic origin is suspected, this classification directs potential genetic screens. ...
Context 2
... behavior of the nuclei of RGCs gives the VZ the appearance of a pseudo-stratified epithelium. A variety of molecules ( Kif1a, Dynein (Tsai et al., 2010 Kosodo et al., 2011)) have been reported to play a role in this process, although since no cortical malformation in human has been shown to our knowledge to be caused directly by abnormal INM (but see discussion below for dynein and LIS1, and Asp in Drosophila (Rujano et al., 2013)), we do not mention them further here. We focus instead on mitosis itself and division occurring at the ventricular lining. ...
Similar publications
The structure of the human neocortex underlies species-specific features and is a reflection of intricate developmental programs. Here we analyzed neocortical cellular lineages through a comprehensive assessment of brain somatic mosaicism—which acts as a neutral recorder of lineage history. We employed deep whole genome and variant sequencing in a...
Citations
... Defects in progenitors can explain reduced brain size (Bizzotto and Francis, 2015), therefore we assessed RG in the L2/+ mouse brain during cortical development. Immunolabeling for Pax6, a transcription factor specific to RG (Götz et al., 1998), was performed on coronal embryonic brain sections of L2/+, L3/+ and WT mice at midcorticogenesis (E14.5). ...
Dynein heavy chain (DYNC1H1) mutations can either lead to severe cerebral cortical malformations, or alternatively may be associated with the development of spinal muscular atrophy with lower extremity predominance (SMA-LED). To assess the origin of such differences, we studied a new Dync1h1 knock-in mouse carrying the cortical malformation p.Lys3334Asn mutation. Comparing with an existing neurodegenerative Dync1h1 mutant (Legs at odd angles, Loa, +/p.Phe580Tyr), we assessed Dync1h1's roles in cortical progenitor and especially radial glia functions during embryogenesis, and assessed neuronal differentiation. p.Lys3334Asn /+ mice exhibit reduced brain and body size. Embryonic brains show increased and disorganized radial glia: interkinetic nuclear migration occurs in mutants, however there are increased basally positioned cells and abventricular mitoses. The ventricular boundary is disorganized potentially contributing to progenitor mislocalization and death. Morphologies of mitochondria and Golgi apparatus are perturbed in vitro, with different effects also in Loa mice. Perturbations of neuronal migration and layering are also observed in p.Lys3334Asn /+ mutants. Overall, we identify specific developmental effects due to a severe cortical malformation mutation in Dync1h1, highlighting the differences with a mutation known instead to primarily affect motor function.
... Perturbations in these sequential steps generate in humans cortical malformations such as lissencephaly, a set of rare brain disorders whereby the whole (agyria) or parts (pachigyria) of the surface of the brain appear smooth [242] and polymicrogyria, a condition characterized by the presence of many and smaller ridges or folds in the brain [243]. ...
Microtubules (MTs) are dynamic components of the cell cytoskeleton involved in several cellular functions, such as structural support, migration and intracellular trafficking. Despite their high similarity, MTs have functional heterogeneity that is generated by the incorporation into the MT lattice of different tubulin gene products and by their post-translational modifications (PTMs). Such regulations, besides modulating the tubulin composition of MTs, create on their surface a “biochemical code” that is translated, through the action of protein effectors, into specific MT-based functions. This code, known as “tubulin code”, plays an important role in neuronal cells, whose highly specialized morphologies and activities depend on the correct functioning of the MT cytoskeleton and on its interplay with a myriad of MT-interacting proteins. In recent years, a growing number of mutations in genes encoding for tubulins, MT-interacting proteins and enzymes that post-translationally modify MTs, which are the main players of the tubulin code, have been linked to neurodegenerative processes or abnormalities in neural migration, differentiation and connectivity. Nevertheless, the exact molecular mechanisms through which the cell writes and, downstream, MT-interacting proteins decipher the tubulin code are still largely uncharted. The purpose of this review is to describe the molecular determinants and the readout mechanisms of the tubulin code, and briefly elucidate how they coordinate MT behavior during critical neuronal events, such as neuron migration, maturation and axonal transport.
... aRG detachment can also be pathological [52,85] leading to ectopic aRG. Very little is known about the involvement of cilia in pathological delamination even though several studies associate PC defects and ectopic aRG or premature or aberrant production of IPs ( [11,87,89,144], see also below). In this section, we focus on PC behaviour related to aRG progeny delamination (e.g., neurons and basal progenitors). ...
Corticogenesis is an intricate process controlled temporally and spatially by many intrinsic and extrinsic factors. Alterations during this important process can lead to severe cortical malformations. Apical neuronal progenitors are essential cells able to self-amplify and also generate basal progenitors and/or neurons. Apical radial glia (aRG) are neuronal progenitors with a unique morphology. They have a long basal process acting as a support for neuronal migration to the cortical plate and a short apical process directed towards the ventricle from which protrudes a primary cilium. This antenna-like structure allows aRG to sense cues from the embryonic cerebrospinal fluid (eCSF) helping to maintain cell shape and to influence several key functions of aRG such as proliferation and differentiation. Centrosomes, major microtubule organising centres, are crucial for cilia formation. In this review, we focus on how primary cilia influence aRG function during cortical development and pathologies which may arise due to defects in this structure. Reporting and cataloguing a number of ciliary mutant models, we discuss the importance of primary cilia for aRG function and cortical development.
... These processes require that newborn neurons are generated, migrate, differentiate and establish neuronal connections at the correct time and place during embryogenesis 1,2 . Perturbations of neuronal migration as well as defects in progenitor function are associated with cortical malformations, which are major causes of developmental disability and epilepsy [3][4][5][6] . ...
Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4 . The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
... Malformations of cortical development are a heterogeneous group of disorders characterized by macroscopic alterations in the brain structure caused by genetic mutations or environmental factors that affect neocortical development (Sun and Hevner, 2014;Bizzotto and Francis, 2015;Desikan and Barkovich, 2016;Romero et al., 2018;Juric-Sekhar and Hevner, 2019;Subramanian et al., 2019;Klingler et al., 2021). Such alterations of brain structure can include abnormal brain size, layering, folding and presence of heterotopic gray matter. ...
... Various genes encoding for centrosomal proteins were found mutated in primary microcephaly (Figure 2A) (Bond et al., 2005;Gilmore and Walsh, 2013;Bizzotto and Francis, 2015). CDK5RAP2 (Cyclin Dependent Kinase 5 Regulatory Subunit Associated Protein 2; MCPH3) and CENPJ (Centromere protein J; MCPH6) are two notable examples (Bond et al., 2005). ...
... Interestingly, the ciliary membrane, which is endocytosed at the onset of mitosis along with the mother centriole, also tends to be inherited by the proliferative daughter cell (Paridaen et al., 2013). Perturbations of ciliary structure or function leads to ciliopathies such as Joubert and Bardet-Biedl syndromes, which can result in cortical disorganization and intellectual disabilities (Taverna et al., 2014;Bizzotto and Francis, 2015). Mutation in centrosomal proteins CENPJ and CEP290 (centrosomal protein 290) have been associated with ciliary phenotypes (Figure 2B). ...
The cerebral cortex is a structure that underlies various brain functions, including cognition and language. Mammalian cerebral cortex starts developing during the embryonic period with the neural progenitor cells generating neurons. Newborn neurons migrate along progenitors’ radial processes from the site of their origin in the germinal zones to the cortical plate, where they mature and integrate in the forming circuitry. Cell biological features of neural progenitors, such as the location and timing of their mitoses, together with their characteristic morphologies, can directly or indirectly regulate the abundance and the identity of their neuronal progeny. Alterations in the complex and delicate process of cerebral cortex development can lead to malformations of cortical development (MCDs). They include various structural abnormalities that affect the size, thickness and/or folding pattern of the developing cortex. Their clinical manifestations can entail a neurodevelopmental disorder, such as epilepsy, developmental delay, intellectual disability, or autism spectrum disorder. The recent advancements of molecular and neuroimaging techniques, along with the development of appropriate in vitro and in vivo model systems, have enabled the assessment of the genetic and environmental causes of MCDs. Here we broadly review the cell biological characteristics of neural progenitor cells and focus on those features whose perturbations have been linked to MCDs.
... Type II lissencephaly, or cobblestone, is typically caused by the defective interaction between the basal end-feet of RGCs and the pial surface, with disruption of the latter. This causes a characteristic overflow of radially migrating neurons past their termination zone below the marginal zone, which traverse through and above the meninges, which confers the appearance of having cobble stones on the cortical surface (241). ...
The human brain is characterized by the large size and intricate folding of its cerebral cortex, which are fundamental for our higher cognitive function and frequently altered in pathological dysfunction. Cortex folding is not unique to humans, nor even to primates, but is common across mammals. Cortical growth and folding are the result of complex developmental processes that involve neural stem and progenitor cells and their cellular lineages, the migration and differentiation of neurons, and the genetic programs that regulate and fine-tune these processes. All these factors combined generate mechanical stress and strain on the developing neural tissue, which ultimately drives orderly cortical deformation and folding. In this review we examine and summarize the current knowledge on the molecular, cellular, histogenic and mechanical mechanisms that are involved in and influence folding of the cerebral cortex, and how they emerged and changed during mammalian evolution. We discuss the main types of pathological malformations of human cortex folding, their specific developmental origin, and how investigating their genetic causes has illuminated our understanding of key events involved. We close our review by presenting the state-of-the-art animal and in vitro models of cortex folding that are currently used to study these devastating developmental brain disorders in children, and what are the main challenges that remain ahead of us to fully understand brain folding.
... In light of the above-mentioned developmental features, the ferret is considered to be a highly suitable model organism for certain neurodevelopmental pathologies. This primarily refers to neocortical malformations (Klingler et al., 2021), which can be a consequence of impaired progenitor proliferation or neuronal migration (Bizzotto and Francis, 2015;Buchsbaum and Cappello, 2019) and affect neocortex size and shape. Since ferrets exhibit an expanded and folded neocortex, they are suitable for modeling diseases such as microcephaly (Johnson et al., 2018) and lissencephaly (Shinmyo et al., 2017). ...
The neocortex is the largest part of the cerebral cortex and a key structure involved in human behavior and cognition. Comparison of neocortex development across mammals reveals that the proliferative capacity of neural stem and progenitor cells and the length of the neurogenic period are essential for regulating neocortex size and complexity, which in turn are thought to be instrumental for the increased cognitive abilities in humans. The domesticated ferret, Mustela putorius furo, is an important animal model in neurodevelopment for its complex postnatal cortical folding, its long period of forebrain development and its accessibility to genetic manipulation in vivo. Here, we discuss the molecular, cellular, and histological features that make this small gyrencephalic carnivore a suitable animal model to study the physiological and pathological mechanisms for the development of an expanded neocortex. We particularly focus on the mechanisms of neural stem cell proliferation, neuronal differentiation, cortical folding, visual system development, and neurodevelopmental pathologies. We further discuss the technological advances that have enabled the genetic manipulation of the ferret in vivo. Finally, we compare the features of neocortex development in the ferret with those of other model organisms.
... Microcephaly is caused by a variety of deleterious disruptions in different cellular processes that affect the amount of neurons produced, including premature depletion and/or death of progenitor cells. Microcephaly has been mostly linked to mutations in genes coding for centrosomal-associated proteins, or microcephalins (MCPH) (Bizzotto & Francis, 2015). For example, mutations in abnormal spindle-like microcephaly associated protein (ASPM) are the most frequent cause of human microcephaly, and ASPM encodes for a protein important to maintain the orientation of the mitotic cleavage plane (Bond et al., 2003;Fish, Kosodo, Enard, P€ a€ abo, & Huttner, 2006). ...
The mammalian cerebral cortex is the pinnacle of brain evolution, reaching its maximum complexity in terms of neuron number, diversity and functional circuitry. The emergence of this outstanding complexity begins during embryonic development, when a limited number of neural stem and progenitor cells manage to generate myriads of neurons in the appropriate numbers, types and proportions, in a process called neurogenesis. Here we review the current knowledge on the regulation of cortical neurogenesis, beginning with a description of the types of progenitor cells and their lineage relationships. This is followed by a review of the determinants of neuron fate, the molecular and genetic regulatory mechanisms, and considerations on the evolution of cortical neurogenesis in vertebrates leading to humans. We finish with an overview on how dysregulation of neurogenesis is a leading cause of human brain malformations and functional disabilities.
... When RG architecture is perturbed apically it can lead to heterotopias associated with epilepsy and sometimes intellectual disability (Bizzotto and Francis, 2015). Firstly, perturbation of RGs and neuron migration can lead to periventricular nodular heterotopia (PH) where clusters of neurons are identified close to the ventricles. ...
... Firstly, perturbation of RGs and neuron migration can lead to periventricular nodular heterotopia (PH) where clusters of neurons are identified close to the ventricles. In PH models, during development abnormal clusters of progenitors and neurons are found trapped at the ventricular surface (Bizzotto and Francis, 2015; Table 2). Secondly, although subcortical band heterotopia (abnormal neuron clusters found within the white matter) is usually associated with an intrinsic problem in migrating neurons, other subcortical heterotopias (SH) can arise due to perturbed and apically detached RG, which subsequently perturb migration (Kielar et al., 2014;Stouffer et al., 2016). ...
During the development of the cortex, newly generated neurons migrate long-distances in the expanding tissue to reach their final positions. Pyramidal neurons are produced from dorsal progenitors, e.g., radial glia (RGs) in the ventricular zone, and then migrate along RG processes basally toward the cortex. These neurons are hence dependent upon RG extensions to support their migration from apical to basal regions. Several studies have investigated how intracellular determinants are required for RG polarity and subsequent formation and maintenance of their processes. Fewer studies have identified the influence of the extracellular environment on this architecture. This review will focus on extracellular factors which influence RG morphology and pyramidal neuronal migration during normal development and their perturbations in pathology. During cortical development, RGs are present in different strategic positions: apical RGs (aRGs) have their cell bodies located in the ventricular zone with an apical process contacting the ventricle, while they also have a basal process extending radially to reach the pial surface of the cortex. This particular conformation allows aRGs to be exposed to long range and short range signaling cues, whereas basal RGs (bRGs, also known as outer RGs, oRGs) have their cell bodies located throughout the cortical wall, limiting their access to ventricular factors. Long range signals impacting aRGs include secreted molecules present in the embryonic cerebrospinal fluid (e.g., Neuregulin, EGF, FGF, Wnt, BMP). Secreted molecules also contribute to the extracellular matrix (fibronectin, laminin, reelin). Classical short range factors include cell to cell signaling, adhesion molecules and mechano-transduction mechanisms (e.g., TAG1, Notch, cadherins, mechanical tension). Changes in one or several of these components influencing the RG extracellular environment can disrupt the development or maintenance of RG architecture on which neuronal migration relies, leading to a range of cortical malformations. First, we will detail the known long range signaling cues impacting RG. Then, we will review how short range cell contacts are also important to instruct the RG framework. Understanding how RG processes are structured by their environment to maintain and support radial migration is a critical part of the investigation of neurodevelopmental disorders.
... These genes are important regulators of glucose, lipid and amino acid metabolism, oxidative phosphorylation, growth factor signaling, reactive oxygen species (ROS) generation, mitochondrial function and integrity, and cell fate [71,72]. The p53-dependent cell death pathway was noted in perturbed progenitors and cortical malformations [73]. Interestingly, human specimens of FCD and animal models have demonstrated aberrant immunoexpressions of p53, which suggests that the p53 signaling pathway plays a crucial role in the pathogenesis of FCD [74]. ...
Focal cortical dysplasia (FCD) is a congenital malformation of cortical development where the cortical neurons located in the brain area fail to migrate in the proper formation. Epilepsy, particularly medically refractory epilepsy, is the most common clinical presentation for all types of FCD. This study aimed to explore the expression change of circulating miRNAs in patients with FCD from serum exosomes. A total of nine patients with FCD and four healthy volunteers were enrolled in this study. The serum exosomes were isolated from the peripheral blood of the subjects. Transmission electron microscopy (TEM) was used to identify the exosomes. Both exosomal markers and neuronal markers were detected by Western blotting analysis to prove that we could obtain central nervous system-derived exosomes from the circulation. The expression profiles of circulating exosomal miRNAs were assessed using next-generation sequencing analysis (NGS). We obtained a total of 107 miRNAs with dominant fold change (>2-fold) from both the annotated 5p-arm and 3p-arm of 2780 mature miRNAs. Based on the integrated platform of HMDD v3.2, miRway DB and DIANA-miRPath v3.0 online tools, and confirmed by MiRBase analysis, four potentially predicted miRNAs from serum exosomes in patients with FCD were identified, including miR194-2-5p, miR15a-5p, miR-132-3p, and miR-145-5p. All four miRNAs presented upregulated expression in patients with FCD compared with controls. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and pathway category of four target miRNAs, we found eight possible signaling pathways that may be related to FCD. Among them, we suggest that the mTOR signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway, and cell cycle regulation and TGF-beta signaling pathway are high-risk pathways that play a crucial role in the pathogenesis of FCD and refractory epilepsy. Our results suggest that the circulating miRNAs from exosomes may provide a potential biomarker for diagnostic, prognostic, and therapeutic adjuncts in patients with FCD and refractory epilepsy.
