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Self-organizing three-dimensional cellular models derived from human pluripotent stem cells or primary tissue have great potential to provide insights into how the human nervous system develops, what makes it unique and how disorders of the nervous system arise, progress and could be treated. Here, to facilitate progress and improve communication with the scientific community and the public, we clarify and provide a basic framework for the nomenclature of human multicellular models of nervous system development and disease, including organoids, assembloids and transplants.

Cellular crosstalk is an essential process influenced by numerous factors, including secreted vesicles that transfer nucleic acids, lipids, and proteins between cells. Extracellular vesicles (EVs) have been the center of many studies focusing on neurodegenerative disorders, but whether EVs display cell-type-specific features for cellular crosstalk during neurodevelopment is unknown. Here, using human-induced pluripotent stem cell-derived cerebral organoids, neural progenitors, neurons, and astrocytes, we identify heterogeneity in EV protein content and dynamics in a cell-type-specific and time-dependent manner. Our results support the trafficking of key molecules via EVs in neurodevelopment, such as the transcription factor YAP1, and their localization to differing cell compartments depending on the EV recipient cell type. This study sheds new light on the biology of EVs during human brain development.

Malformations of the human cortex represent a major cause of disability1. Mouse models with mutations in known causal genes only partially recapitulate the phenotypes and are therefore not unlimitedly suited for understanding the molecular and cellular mechanisms responsible for these conditions2. Here we study periventricular heterotopia (PH) by analyzing cerebral organoids derived from induced pluripotent stem cells (iPSCs) of patients with mutations in the cadherin receptor–ligand pair DCHS1and FAT4or from isogenic knockout (KO) lines1,3. Our results show that human cerebral organoids reproduce the cortical heterotopia associated with PH. Mutations in DCHS1and FAT4or knockdown of their expression causes changes in the morphology of neural progenitor cells and result in defective neuronal migration dynamics only in a subset of neurons. Single-cell RNA-sequencing (scRNA-seq) data reveal a subpopulation of mutant neurons with dysregulated genes involved in axon guidance, neuronal migration and patterning. We suggest that defective neural progenitor cell (NPC) morphology and an altered navigation system in a subset of neurons underlie this form of PH.

Rho-GTPases have been found to be crucial for cytoskeleton remodelling and cell polarity, as well as key players in directed cell migration in various tissues and organs, therefore becoming good candidates for involvement in neuronal migration disorders. We recently found that genetic deletion of the small GTPase RhoA in the developing mouse cerebral cortex results in three distinct cortical malformations: a defect in the proliferation of progenitor cells during development that leads to a bigger cerebral cortex in the adult mouse, a change in the morphology of radial glial cells that results in the formation of a subcortical band heterotopia (SBH, also called Double Cortex) and an increase in the speed of migrating newborn neurons. The latter, together with the aberrant radial glial shape, is likely to be the cause of cobblestone lissencephaly, where neurons protrude beyond layer I at the pial surface of the brain.

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 DiversityNervous System Development > Vertebrates: General Principles Brain organoids are 3D tissue cultures generated from human induced pluripotent stem cells and can recapitulate the basic steps of the developing human brain. They can be used as a human‐specific model for studying brain development, evolution and disease.

The mammalian neocortex has undergone remarkable changes through evolution. A consequence of such rapid evolutionary events could be a trade-off that has rendered the brain susceptible to certain neurodevelopmental and neuropsychiatric conditions. We analyzed the exomes of 65 patients with the structural brain malformation periventricular nodular heterotopia (PH). De novocoding variants were observed in excess in genes defining a transcriptomic signature of basal radial glia, a cell type linked to brain evolution. In addition, we located two variants in human isoforms of two genes that have no ortholog in mice. Modulating the levels of one of these isoforms for the gene PLEKHG6demonstrated its role in regulating neuroprogenitor differentiation and neuronal migration via RhoA, with phenotypic recapitulation of PH in human cerebral organoids. This suggests that this PLEKHG6isoform is an example of a primate-specific genomic element supporting brain development.