The cerebral cortex is an intricate structure that controls human features such as language and cognition. Cortical functions rely on specialized neurons that emerge during development from complex ...molecular and cellular interactions. Neurodevelopmental disorders occur when one or several of these steps is incorrectly executed. Although a number of causal genes and disease phenotypes have been identified, the sequence of events linking molecular disruption to clinical expression mostly remains obscure. Here, focusing on human malformations of cortical development, we illustrate how complex interactions at the genetic, cellular, and circuit levels together contribute to diversity and variability in disease phenotypes. Using specific examples and an online resource, we propose that a multilevel assessment of disease processes is key to identifying points of vulnerability and developing new therapeutic strategies.
•Update in cortical development malformations (MCDs) involving single gene mutations.•Comparative description of animal models of the main mutated genes.•Atypical rare mutations leading to neuronal ...migration phenotypes.•Genetics, mouse models and human cell models as tools to understand mechanisms of MCD.•Non-genetic mechanisms of MCD, the case of Zika virus infection.
Cerebral cortical development involves a complex series of highly regulated steps to generate the laminated structure of the adult neocortex. Neuronal migration is a key part of this process. We provide here a detailed review of cortical malformations thought to be linked to abnormal neuronal migration. We have focused on providing updated views related to perturbed mechanisms based on the wealth of genetic information currently available, as well as the study of mutant genes in animal models. We discuss mainly type 1 lissencephaly, periventricular heterotopia, type II lissencephaly and polymicrogyria. We also discuss functional classifications such as the tubulinopathies, and emphasize how modern genetics is revealing genes mutated in atypical cases, as well as unexpected genes for classical cases. A role in neuronal migration is revealed for many mutant genes, although progenitor abnormalities also predominate, depending on the disorder. We finish by describing the advantages of human in vitro cell culture models, to examine human-specific cells and transcripts, and further mention non-genetic mechanisms leading to cortical malformations.
The development of the cerebral cortex relies on different types of progenitor cell. Among them, the recently described basal radial glial cell (bRG) is suggested to be of critical importance for the ...development of the brain in gyrencephalic species. These cells are highly numerous in primate and ferret brains, compared to lissencephalic species such as the mouse in which they are few in number. Their somata are located in basal subventricular zones in gyrencephalic brains and they generally possess a basal process extending to the pial surface. They sometimes also have an apical process directed toward the ventricular surface, similar to apical radial glial cells (aRGs) from which they are derived, and whose somata are found more apically in the ventricular zone. bRGs share similarities with aRGs in terms of gene expression (
,
, and
), whilst also expressing a range of more specific genes (such as
). In primate brains, bRGs can divide multiple times, self-renewing and/or generating intermediate progenitors and neurons. They display a highly specific cytokinesis behavior termed mitotic somal translocation. We focus here on recently identified molecular mechanisms associated with the generation and amplification of bRGs, including bRG-like cells in the rodent. These include signaling pathways such as the FGF-MAPK cascade, SHH, PTEN/AKT, PDGF pathways, and proteins such as INSM, GPSM2, ASPM, TRNP1, ARHGAP11B, PAX6, and HIF1α. A number of these proteins were identified through transcriptome comparisons in human aRGs vs. bRGs, and validated by modifying their activities or expression levels in the mouse. This latter experiment often revealed enhanced bRG-like cell production, even in some cases generating folds (gyri) on the surface of the mouse cortex. We compare the features of the identified cells and methods used to characterize them in each model. These important data converge to indicate pathways essential for the production and expansion of bRGs, which may help us understand cortical development in health and disease.
The cerebral cortex is a highly organized structure whose development depends on diverse progenitor cell types, namely apical radial glia, intermediate progenitors, and basal radial glia cells, which ...are responsible for the production of the correct neuronal output. In recent years, these progenitor cell types have been deeply studied, particularly basal radial glia and their role in cortical expansion and gyrification. We review here a broad series of factors that regulate progenitor behavior and daughter cell fate. We first describe the different neuronal progenitor types, emphasizing the differences between lissencephalic and gyrencephalic species. We then review key factors shown to influence progenitor proliferation versus differentiation, discussing their roles in progenitor dynamics, neuronal production, and potentially brain size and complexity. Although spindle orientation has been considered a critical factor for mode of division and daughter cell output, we discuss other features that are emerging as crucial for these processes such as organelle and cell cycle dynamics. Additionally, we highlight the importance of adhesion molecules and the polarity complex for correct cortical development. Finally, we briefly discuss studies assessing progenitor multipotency and its possible contribution to the production of specific neuronal populations. This review hence summarizes recent aspects of cortical progenitor cell biology, and pinpoints emerging features critical for their behavior.
In this review, we focus on the exquisite regulation between the different cortical neuronal progenitor types, namely apical radial glia, intermediate progenitors, and basal radial glia, the latter being characteristic of species with bigger and more complex brains, containing gyri and sulci. We review key progenitor features, recently described to influence transitions between them and to mediate proliferation versus differentiation toward a more committed state in the neuronal lineage. Although spindle orientation has been considered important to regulate daughter cell output, other features are also being revealed as crucial to determine cell fate, such as extracellular cues, and organelle and cell cycle dynamics. In addition, adhesion and polarity complex molecules are clearly critical to assure correct cortex development. This new review summarizes diverse and current aspects of neuronal progenitor cell biology, while pinpointing emerging features regulating key steps related to these important cell types.
Abstract A wide spectrum of focal, regional, or diffuse structural brain abnormalities, collectively known as malformations of cortical development (MCDs), frequently manifest with intellectual ...disability (ID), epilepsy, and/or autistic spectrum disorder (ASD). As the acronym suggests, MCDs are perturbations of the normal architecture of the cerebral cortex and hippocampus. The pathogenesis of these disorders remains incompletely understood; however, one area that has provided important insights has been the study of neuronal migration. The amalgamation of human genetics and experimental studies in animal models has led to the recognition that common genetic causes of neurodevelopmental disorders, including many severe epilepsy syndromes, are due to mutations in genes regulating the migration of newly born post-mitotic neurons. Neuronal migration genes often, though not exclusively, code for proteins involved in the function of the cytoskeleton. Other cellular processes, such as cell division and axon/dendrite formation, which similarly depend on cytoskeletal functions, may also be affected. We focus here on how the susceptibility of the highly organized neocortex and hippocampus may be due to their laminar organization, which involves the tight regulation, both temporally and spatially, of gene expression, specialized progenitor cells, the migration of neurons over large distances and a birthdate-specific layering of neurons. Perturbations in neuronal migration result in abnormal lamination, neuronal differentiation defects, abnormal cellular morphology and circuit formation. Ultimately this results in disorganized excitatory and inhibitory activity leading to the symptoms observed in individuals with these disorders.
Glass sponge gardens are important biogenic habitats that support fish communities in Pacific Canada. However, glass sponges (class Hexactinellida) are delicate and susceptible to damage from fishing ...gear such as downriggers. In this study we document changes in a fish community before –and after damage from a presumed fishing event that resulted in a reduction of 58.9% of the available sponge habitat in a small cloud sponge garden in British Columbia. This habitat loss coincided with a decline of 76.9% of the relative abundance of rockfish, an economically important group of fishes, at the garden. This decline was particularly pronounced in small size classes with the disappearance of juvenile rockfish after the sponge loss. Although based on a single site, this is the first documentation of how anthropogenic damage in a sponge aggregation may impact the associated fish community. Damage from fishing gear is likely most pronounced in small sponge aggregations, like nearshore gardens, where a single event may result in a disproportionately large loss of available fish habitat. Slow regrowth of sponges suggests the habitat availability may be permanently altered at these sites and can coincide with shifts in the localized fish community that may be long lasting on a local scale. Currently sponge gardens do not have any direct spatial protections in the Pacific Northwest, and this work highlights the importance of considering them in future protection initiatives.
•Paper Highlights.•Glass sponge gardens are biogenic habitats susceptible to damage from fishing gear.•Sponge loss from fishing coincided with a decline in associated rockfish abundance.•Rockfish declines were most pronounced in juvenile rockfish size classes.•Protection measures should consider sponge gardens to conserve sponges and rockfish.
Abstract
Human cerebral cortical malformations are associated with progenitor proliferation and neuronal migration abnormalities. Progenitor cells include apical radial glia, intermediate progenitors ...and basal (or outer) radial glia (bRGs or oRGs). bRGs are few in number in lissencephalic species (e.g. the mouse) but abundant in gyrencephalic brains. The LIS1 gene coding for a dynein regulator, is mutated in human lissencephaly, associated also in some cases with microcephaly. LIS1 was shown to be important during cell division and neuronal migration. Here, we generated bRG-like cells in the mouse embryonic brain, investigating the role of Lis1 in their formation. This was achieved by in utero electroporation of a hominoid-specific gene TBC1D3 (coding for a RAB-GAP protein) at mouse embryonic day (E) 14.5. We first confirmed that TBC1D3 expression in wild-type (WT) brain generates numerous Pax6+ bRG-like cells that are basally localized. Second, using the same approach, we assessed the formation of these cells in heterozygote Lis1 mutant brains. Our novel results show that Lis1 depletion in the forebrain from E9.5 prevented subsequent TBC1D3-induced bRG-like cell amplification. Indeed, we observe perturbation of the ventricular zone (VZ) in the mutant. Lis1 depletion altered adhesion proteins and mitotic spindle orientations at the ventricular surface and increased the proportion of abventricular mitoses. Progenitor outcome could not be further altered by TBC1D3. We conclude that disruption of Lis1/LIS1 dosage is likely to be detrimental for appropriate progenitor number and position, contributing to lissencephaly pathogenesis.
The stalked tunicate Boltenia ovifera is widely distributed in the Arctic and North Atlantic oceans on rocky substrata at 10–300 m depth, although its ecological role in benthic communities is poorly ...understood. The distribution and abundance of B. ovifera were recorded at 10–100 m depth in towed-video transects in November 2011 and in June, July, and November 2012 off a wave-exposed headland near Halifax, Nova Scotia. Specimens also were collected at 30 m depth using SCUBA (44°26.88′N, 63°31.59′W) in September 2012. Areas dominated by B. ovifera had densities of 10–100 individuals m⁻² on rocky substrata at 30–60 m depth. These tunicate beds often were associated with sparse kelp (Agarum clathratum) and turf-forming red algae. A generalized additive model indicated that depth, substrate type, and benthic algal type were strong predictors of tunicate abundance. Twenty-two epibiotic species were found on specimens of B. ovifera, including juvenile conspecifics. Filter-feeding macroinvertebrates, including anemones and soft corals, were more abundant in areas with B. ovifera than in areas without these tunicates. Our findings suggest that beds of B. ovifera can act as biogenic habitat to enhance local species richness in the rocky subtidal zone of Nova Scotia.
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 characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area.
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