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Mutations in the human progranulin (GRN) gene are a leading cause of frontotemporal lobar degeneration (FTLD). While previous studies implicate aberrant microglial activation as a disease-driving factor in neurodegeneration in the thalamocortical circuit in [Grn.sup.-/-] mice, the exact mechanism for neurodegeneration in FTLD-GRN remains unclear. By performing comparative single-cell transcriptomics in the thalamus and frontal cortex of [Grn.sup.-/-] mice and patients with FTLD-GRN, we have uncovered a highly conserved astroglial pathology characterized by upregulation of gap junction protein GJA1, water channel AQP4, and lipid-binding protein APOE, and downregulation of glutamate transporter SLC1A2 that promoted profound synaptic degeneration across the two species. This astroglial toxicity could be recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced pluripotent stem cell-derived astrocytes to cortical organoids, where progranulin-deficient astrocytes promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy. Together, these results reveal a previously unappreciated astroglial pathology as a potential key mechanism in neurodegeneration in FTLD-GRN., Introduction Frontotemporal dementia (FTD) is a common neurodegenerative disease in patients under 65 years of age. The clinical manifestations of FTD include progressive behavioral changes and deterioration in language skills [...]

Author(s): Jan H. Lui [1]; Tomasz J. Nowakowski [1]; Alex A. Pollen [1]; Ashkan Javaherian [1]; Arnold R. Kriegstein (corresponding author) [1]; Michael C. Oldham (corresponding author) [1] Evolutionary expansion [...]

Ring chromosomes are structural aberrations commonly associated with birth defects, mental disabilities and growth retardation (1,2). Rings form after fusion of the long and short arms of a chromosome, and are sometimes associated with large terminal deletions (2). Owing to the severity of these large aberrations that can affect multiple contiguous genes, no possible therapeutic strategies for ring chromosome disorders have been proposed. During cell division, ring chromosomes can exhibit unstable behaviour leading to continuous production of aneuploid progeny with low viability and high cellular death rate (3-9). The overall consequences of this chromosomal instability have been largely unexplored in experimental model systems. Here we generated human induced pluripotent stem cells (iPSCs) (10-12) from patient fibroblasts containing ring chromosomes with large deletions and found that reprogrammed cells lost the abnormal chromosome and duplicated the wild-type homologue through the compensatory uniparental disomy (UPD) mechanism. The karyotypically normal iPSCs with isodisomy for the corrected chromosome outgrew co-existing aneuploid populations, enabling rapid and efficient isolation of patient-derived iPSCs devoid of the original chromosomal aberration. Our results suggest a fundamentally different function for cellular reprogramming as a means of 'chromosome therapy' (13) to reverse combined loss-of-function across many genes in cells with large-scale aberrations involving ring structures. In addition, our work provides an experimentally tractable human cellular system for studying mechanisms of chromosomal number control, which is of critical relevance to human development and disease., We obtained fibroblasts from a Miller Dieker Syndrome (MDS) patient with ring chromosome 17, subsequently referred to as r(17). MDS is caused by heterozygous deletions of human band 17p13.3 (refs [...]

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.The nomenclature for human multicellular models of nervous system development and disease, including organoids, assembloids and transplants, is discussed and a consensus framework is presented. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a flavivirus transmitted via mosquitoes and sex to cause congenital neurodevelopmental defects, including microcephaly. Inherited forms of microcephaly (MCPH) are associated with disrupted centrosome organization. Similarly, we found that ZIKV infection disrupted centrosome organization. ZIKV infection disrupted the organization of centrosomal proteins including CEP63, a MCPH‐associated protein. The ZIKV nonstructural protein NS3 bound CEP63, and expression of NS3 was sufficient to alter centrosome architecture and CEP63 localization. Loss of CEP63 suppressed ZIKV‐induced centrosome disorganization, indicating that ZIKV requires CEP63 to disrupt centrosome organization. ZIKV infection or CEP63 loss decreased the centrosomal localization and stability of TANK‐binding kinase 1 (TBK1), a regulator of the innate immune response. ZIKV infection also increased the centrosomal accumulation of the CEP63 interactor DTX4, a ubiquitin ligase that degrades TBK1. Therefore, we propose that ZIKV disrupts CEP63 function to increase centrosomal DTX4 localization and destabilization of TBK1, thereby tempering the innate immune response. Synopsis: Brazilian Zika virus (ZIKV) infection disrupts centrosome organization and destabilizes TBK1, thereby dampening innate immune response activation. ZIKV protein NS3 localizes to the centrosome and redistributes the microcephaly‐associated protein CEP63 from the centrosome.Acentrosomal CEP63 recruits the ubiquitin ligase DTX4 leading to the degradation of TBK1, a regulator of innate immunity.TBK1 loss prevents the activation of the innate immune response in ZIKV‐infected cells. [ABSTRACT FROM AUTHOR]

Author(s): Shawn F. Sorrells [1, 2]; Mercedes F. Paredes [1, 3]; Arantxa Cebrian-Silla [4]; Kadellyn Sandoval [1, 3]; Dashi Qi [5]; Kevin W. Kelley [1]; David James [1]; Simone Mayer [...]

Organoids are 3D cell culture systems derived from human pluripotent stem cells that contain tissue resident cell types and reflect features of early tissue organization. Neural organoids are a particularly innovative scientific advance given the lack of accessibility of developing human brain tissue and intractability of neurological diseases. Neural organoids have become an invaluable approach to model features of human brain development that are not well reflected in animal models. Organoids also hold promise for the study of atypical cellular, molecular, and genetic features that underscore neurological diseases. Additionally, organoids may provide a platform for testing therapeutics in human cells and are a potential source for cell replacement approaches to brain injury or disease. Despite the promising features of organoids, their broad utility is tempered by a variety of limitations yet to be overcome, including lack of high-fidelity cell types, limited maturation, atypical physiology, and lack of arealization, features that may limit their reliability for certain applications. [ABSTRACT FROM AUTHOR]

Oligodendrocytes and astrocytes are macroglial cells of the vertebrate central nervous system. These cells have diverse roles in the maintenance of neurological function. In the embryo, the genetic mechanisms that underlie the specification of macroglial precursors in vivo appear strikingly similar to those that regulate the development of the diverse neuron types. The switch from producing neuronal to glial subtype-specific precursors can be modelled as an interplay between region-restricted components and temporal regulators that determine neurogenic or gliogenic phases of development, contributing to glial diversity. Gaining insight into the developmental genetics of macroglia has great potential to improve our understanding of a variety of neurological disorders in humans., Glia make up 10-20% of the cells in the Drosophila nervous system and at least 50% of the cells in the human brain. These findings indicate that glial-cell function is [...]

Neurons in the developing rodent cortex are generated from radial glial cells that function as neural stem cells. These epithelial cells line the cerebral ventricles and generate intermediate progenitor cells that migrate into the subventricular zone (SVZ) and proliferate to increase neuronal number. The developing human SVZ has a massively expanded outer region (OSVZ) thought to contribute to cortical size and complexity. However, OSVZ progenitor cell types and their contribution to neurogenesis are not well understood. Here we show that large numbers of radial glia-like cells and intermediate progenitor cells populate the human OSVZ. We find that OSVZ radial glia-like cells have a long basal process but, surprisingly, are non-epithelial as they lack contact with the ventricular surface. Using real-time imaging and clonal analysis, we demonstrate that these cells can undergo proliferative divisions and self-renewing asymmetric divisions to generate neuronal progenitor cells that can proliferate further. We also show that inhibition of Notch signalling in OSVZ progenitor cells induces their neuronal differentiation. The establishment of non-ventricular radial glia-like cells may have been a critical evolutionary advance underlying increased cortical size and complexity in the human brain., One of the most marked evolutionary changes underlying the unique cognitive abilities of humans is the greatly enlarged cerebral cortex. This change must be reflected in differences in progenitor cell [...]

The morphological development of the cerebral cortex from a primitive neuroepithelium into a complex laminar structure underlying higher cognition must rely on a network of intercellular signaling. Gap junctions are widely expressed during embryonic development and provide a means of cell-cell contact and communication. We review the roles of gap junctions in regulating the proliferation of neural progenitors as well as the migration and differentiation of young neurons in the embryonic cerebral cortex. There is substantial evidence that although gap junctions act in the classical manner coupling neural progenitors, they also act as hemichannels mediating the spread of calcium waves across progenitor cell populations and as adhesive molecules aiding neuronal migration. Gap junctions are thus emerging as multifaceted regulators of cortical development playing diverse roles in intercellular communication.

Radial glial cells, the stem cells of the cerebral cortex, extend a long basal fiber that ends in basal endfeet. A new study in PLOS Biology found that non-muscle myosins control basal endfoot integrity to regulate interneuron organization. Radial glial cells, the stem cells of the cerebral cortex, extend a long basal fiber that ends in basal endfeet. This Primer explores the implications of a new PLOS Biology study revealing that non-muscle myosins control basal endfoot integrity to regulate interneuron organization. [ABSTRACT FROM AUTHOR]

Author(s): Laura A. B. Elias (corresponding author) [1, 2]; Doris D. Wang [1, 2]; Arnold R. Kriegstein (corresponding author) [2] During neocortical brain development, radial glia, which reside in the [...]

Real-time imaging of migrating neurons has changed our understanding of how newborn neurons reach their final positions in the developing cerebral cortex. The migratory routes and modes of migration are more diverse and complex than previously thought. The finding that cortical interneurons migrate to the cortex from origins in the ventral telencephalon has already markedly altered our view of cortical migration. More recent findings have demonstrated additional nuances in the migratory pattern and highlighted differences between subsets of interneurons. Moreover, radial migration of pyramidal neurons does not progress smoothly from ventricle to cortical plate, but is instead characterized by distinct migratory phases in which neurons change shape and direction of movement. Integrating these findings with the molecular machinery underlying migration will provide a more complete picture of how the cerebral cortex is assembled.

Author(s): Stephen C. Noctor [1]; Alexander C. Flint [1]; Tamily A. Weissman [2]; Ryan S. Dammerman [2]; Arnold R. Kriegstein (corresponding author) [1, 2, 3] The neocortex of the adult [...]