GNG5 Controls the Number of Apical and Basal Progenitors and Alters Neuronal Migration During Cortical Development

Cortical development is a very complex process in which any temporal or spatial alterations can give rise to a wide range of cortical malformations. Among those malformations, periventricular heterotopia (PH) is characterized by clusters of neurons that do not migrate to the correct place. Cerebral organoids derived from patients with mutations in DCHS1 and FAT4, which have been associated with PH, exhibit higher levels of GNG5 expression in a patient-specific cluster of neurons. Here we investigate the role of GNG5 during the development of the cerebral cortex in mice and human cerebral organoids. GNG5, highly expressed in progenitors and downregulated in neurons, is critical for controlling the number of apical and basal progenitors and neuronal migration. Moreover, forced expression of GNG5 recapitulates some of the alterations observed upon downregulation of Dchs1 and Fat4 in mice and human cerebral organoids derived from DCHS1 and FAT4 patients, suggesting a critical role of GNG5 in cortical development

Large Eddy Simulations of sediment entrainment induced by a lock-exchange gravity current

Large Eddy simulations of lock-exchange gravity currents propagating over a mobile reach are presented. The numerical setting allows to investigate the sediment pick up induced by the currents and to study the underlying mechanisms leading to sediment entrainment for different Grashof numbers and grain sizes. First, the velocity field and the bed shear-stress distribution are investigated, along with turbulent structures formed in the flow, before the current reaches the mobile bed. Then, during the propagation of the current above the erodible section of the bed the contour plots of the entrained material are pre- sented as well as the time evolution of the areas covered by the current and by the sediment at this section. The numerical outcomes are compared with experimental data showing a very good agreement. Overall, the study confirms that sediment pick up is prevalent at the head of the current where the strongest turbulence occurs. Further, above the mobile reach of the bed, settling process seems to be of minor importance, with the entrained material being advected downstream by the current. Additionally, the study shows that, although shear stress is the main mechanism that sets particles in motion, turbu- lent bursts as well as vertical velocity fluctuations are also necessary to counteract the falling velocity of the particles and maintain them into suspension. Finally, the analysis of the stability conditions of the current shows that, from one side, sediment concentration gives a negligible contribution to the stability of the front of the current and from the other side, the stability conditions provided by the current do not allow sediments to move into the ambient fluid

Non-cell-autonomous regulation of interneuron specification mediated by extracellular vesicles

Disruption in neurogenesis and neuronal migration can influence the assembly of cortical circuits, affecting the excitatory-inhibitory balance and resulting in neurodevelopmental and neuropsychiatric disorders. Using ventral cerebral organoids and dorsoventral cerebral assembloids with mutations in the extracellular matrix gene LGALS3BP, we show that extracellular vesicles released into the extracellular environment regulate the molecular differentiation of neurons, resulting in alterations in migratory dynamics. To investigate how extracellular vesicles affect neuronal specification and migration dynamics, we collected extracellular vesicles from ventral cerebral organoids carrying a mutation in LGALS3BP, previously identified in individuals with cortical malformations and neuropsychiatric disorders. These results revealed differences in protein composition and changes in dorsoventral patterning. Proteins associated with cell fate decision, neuronal migration, and extracellular matrix composition were altered in mutant extracellular vesicles. Moreover, we show that treatment with extracellular vesicles changes the transcriptomic profile in neural progenitor cells. Our results indicate that neuronal molecular differentiation can be influenced by extracellular vesicles

Mob2 Insufficiency Disrupts Neuronal Migration in the Developing Cortex

Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor-MOB2-in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown of Mob2 within the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development

Extracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity.

Basal progenitors (BPs), including intermediate progenitors and basal radial glia, are generated from apical radial glia and are enriched in gyrencephalic species like humans, contributing to neuronal expansion. Shortly after generation, BPs delaminate towards the subventricular zone, where they further proliferate before differentiation. Gene expression alterations involved in BP delamination and function in humans are poorly understood. Here, we study the role of LGALS3BP, so far known as a cancer biomarker, which is a secreted protein enriched in human neural progenitors (NPCs). We show that individuals with LGALS3BP de novo variants exhibit altered local gyrification, sulcal depth, surface area and thickness in their cortex. Additionally, using cerebral organoids, human fetal tissues and mice, we show that LGALS3BP regulates the position of NPCs. Single-cell RNA-sequencing and proteomics reveal that LGALS3BP-mediated mechanisms involve the extracellular matrix in NPCs' anchoring and migration within the human brain. We propose that its temporal expression influences NPCs' delamination, corticogenesis and gyrification extrinsically

Using brain organoids to study human neurodevelopment, evolution and disease

The brain is one of the most complex organs, responsible for the advanced intellectual and cognitive ability of humans. Although primates are to some extent capable of performing cognitive tasks, their abilities are less evolved. One of the reasons for this is the vast differences in the brain of humans compared to other mammals, in terms of shape, size and complexity. Such differences make the study of human brain development fascinating. Interestingly, the cerebral cortex is by far the most complex brain region resulting from its selective evolution within mammals over millions of years. Unraveling the molecular and cellular mechanisms regulating brain development, as well as the evolutionary differences seen across species and the need to understand human brain disorders, are some of the reasons why scientists are interested in improving their current knowledge on human corticogenesis. Toward this end, several animal models including primates have been used, however, these models are limited in their extent to recapitulate human-specific features. Recent technological achievements in the field of stem cell research, which have enabled the generation of human models of corticogenesis, called brain or cerebral organoids, are of great importance. This review focuses on the main cellular and molecular features of human corticogenesis and the use of brain organoids to study it. We will discuss the key differences between cortical development in human and nonhuman mammals, the technological applications of brain organoids and the different aspects of cortical development in normal and pathological conditions, which can be modeled using brain organoids. This article is categorized under: Comparative Development and Evolution > Regulation of Organ Diversity Nervous System Development > Vertebrates: General Principle

Profilin1-Dependent F-Actin Assembly Controls Division of Apical Radial Glia and Neocortex Development

Neocortex development depends on neural stem cell proliferation, cell differentiation, neurogenesis, and neuronal migration. Cytoskeletal regulation is critical for all these processes, but the underlying mechanisms are only poorly understood. We previously implicated the cytoskeletal regulator profilin1 in cerebellar granule neuron migration. Since we found profilin1 expressed throughout mouse neocortex development, we here tested the hypothesis that profilin1 is crucial for neocortex development. We found no evidence for impaired neuron migration or layering in the neocortex of profilin1 mutant mice. However, proliferative activity at basal positions was doubled in the mutant neocortex during mid-neurogenesis, with a drastic and specific increase in basal Pax6(+) cells indicative for elevated numbers of basal radial glia (bRG). This was accompanied by transiently increased neurogenesis and associated with mild invaginations resembling rudimentary neocortex folds. Our data are in line with a model in which profilin1-dependent actin assembly controls division of apical radial glia (aRG) and thereby the fate of their progenies. Via this mechanism, profilin1 restricts cell Co delamination from the ventricular surface and, hence, bRG production and thereby controls neocortex development in mice. Our data support the radial cone hypothesis claiming that elevated bRG number causes neocortex folds

Mcidas and GemC1 are key regulators for the generation of multiciliated ependymal cells in the adult neurogenic niche.

Multiciliated cells are abundant in the epithelial surface of different tissues, including cells lining the walls of the lateral ventricles in the brain and the airway epithelium. Their main role is to control fluid flow and defects in their differentiation are implicated in many human disorders, such as hydrocephalus, accompanied by defects in adult neurogenesis and mucociliary disorder in the airway system. Here we show that Mcidas, which is mutated in human mucociliary clearance disorder, and GemC1 (Gmnc or Lynkeas), previously implicated in cell cycle progression, are key regulators of multiciliated ependymal cell generation in the mouse brain. Overexpression and knockdown experiments show that Mcidas and GemC1 are sufficient and necessary for cell fate commitment and differentiation of radial glial cells to multiciliated ependymal cells. Furthermore, we show that GemC1 and Mcidas operate in hierarchical order, upstream of Foxj1 and c-Myb transcription factors, which are known regulators of ependymal cell generation, and that Notch signaling inhibits GemC1 and Mcidas function. Our results suggest that Mcidas and GemC1 are key players in the generation of multiciliated ependymal cells of the adult neurogenic niche