Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain.

Background: Genetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A).

Spatial and cell type transcriptional landscape of human cerebellar development.

The human neonatal cerebellum is one-fourth of its adult size yet contains the blueprint required to integrate environmental cues with developing motor, cognitive and emotional skills into adulthood. Although mature cerebellar neuroanatomy is well studied, understanding of its developmental origins is limited. In this study, we systematically mapped the molecular, cellular and spatial composition of human fetal cerebellum by combining laser capture microscopy and SPLiT-seq single-nucleus transcriptomics.

Neural Stem Cells Direct Axon Guidance via Their Radial Fiber Scaffold.

Neural stem cells directly or indirectly generate all neurons and macroglial cells and guide migrating neurons by using a palisade-like scaffold made of their radial fibers. Here, we describe an unexpected role for the radial fiber scaffold in directing corticospinal and other axons at the junction between the striatum and globus pallidus. The maintenance of this scaffold, and consequently axon pathfinding, is dependent on the expression of an atypical RHO-GTPase, RND3/RHOE, together with its binding partner ARHGAP35/P190A, a RHO GTPase-activating protein, in the radial glia-like neural stem cells within the ventricular zone of the medial ganglionic eminence.

Whole-Genome and RNA Sequencing Reveal Variation and Transcriptomic Coordination in the Developing Human Prefrontal Cortex.

Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development.

Spatiotemporal transcriptomic divergence across human and macaque brain development.

Human nervous system development is an intricate and protracted process that requires precise spatiotemporal transcriptional regulation. We generated tissue-level and single-cell transcriptomic data from up to 16 brain regions covering prenatal and postnatal rhesus macaque development. Integrative analysis with complementary human data revealed that global intraspecies (ontogenetic) and interspecies (phylogenetic) regional transcriptomic differences exhibit concerted cup-shaped patterns, with a late fetal-to-infancy (perinatal) convergence.

Integrative functional genomic analysis of human brain development and neuropsychiatric risks.

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations.

Evolution of the Human Nervous System Function, Structure, and Development.

The nervous system-in particular, the brain and its cognitive abilities-is among humans' most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits.

Zika Virus Disrupts Phospho-TBK1 Localization and Mitosis in Human Neuroepithelial Stem Cells and Radial Glia.

The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related neuropathogenesis. By analyzing human NES cells, organotypic fetal brain slices, and a ZIKV-infected micrencephalic brain, we show that ZIKV infects both neocortical and spinal NES cells as well as their fetal homolog, radial glial cells (RGCs), causing disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death.

From trans to cis: transcriptional regulatory networks in neocortical development.

Transcriptional mechanisms mediated by the binding of transcription factors (TFs) to cis-acting regulatory elements (CREs) in DNA play crucial roles in directing gene expression. While TFs have been extensively studied, less effort has gone towards the identification and functional characterization of CREs and associated epigenetic modulation. However, owing to methodological and analytical advances, more comprehensive studies of regulatory elements and mechanisms are now possible.

The cortical hem regulates the size and patterning of neocortex.

The cortical hem, a source of Wingless-related (WNT) and bone morphogenetic protein (BMP) signaling in the dorsomedial telencephalon, is the embryonic organizer for the hippocampus. Whether the hem is a major regulator of cortical patterning outside the hippocampus has not been investigated. We examined regional organization across the entire cerebral cortex in mice genetically engineered to lack the hem.

Rapid selection response for contextual fear conditioning in a cross between C57BL/6J and A/J: behavioral, QTL and gene expression analysis.

We used short-term selection to produce outbred mouse lines with differences in contextual fear conditioning. Within two generations of selection all low selected mice were homozygous for the recessive tyrc allele and showed the corresponding albino coat color. Freezing differed in the high and low selected lines across a range of parameters.

The mouse Engrailed genes: a window into autism.

The complex behavioral symptoms and neuroanatomical abnormalities observed in autistic individuals strongly suggest a multi-factorial basis for this perplexing disease. Although not the perfect model, we believe the Engrailed genes provide an invaluable "window" into the elusive etiology of autism spectrum disorder. The Engrailed-2 gene has been associated with autism in genetic linkage studies.

A genetic study of the suppressors of the Engrailed-1 cerebellar phenotype.

The mouse Engrailed genes, En1 and En2, play an important role in the development of the cerebellum from its inception at the mid/hindbrain boundary in early embryonic development through cell type specification events and beyond. In the absence of En1, the cerebellum and caudal midbrain fail to develop normally--a phenotype that we have previously reported to be strain dependent. On the 129/S1 strain background, En1 null alleles lead to mid/hindbrain failure, whereas on the C57BL/6 background, En1 deficiency is compatible with near normal cerebellar development.

A question of balance: a proposal for new mouse models of autism.

Autism spectrum disorder (ASD) represents a major mental health problem with estimates of prevalence ranging from 1/500 to 1/2000. While generally recognized as developmental in origin, little to nothing is certain about its etiology. Currently, diagnosis is made on the basis of a variety of early developmental delays and/or regressions in behavior.

R5 HIV productively infects Langerhans cells, and infection levels are regulated by compound CCR5 polymorphisms.

Langerhans cells (LCs) are suspected to be initial targets for HIV after sexual exposure (by becoming infected or by capturing virus). Here, productive R5 HIV infection of LC ex vivo and LC-mediated transmission of virus to CD4+ T cells were both found to depend on CCR5. By contrast, infection of monocyte-derived dendritic cells and transfer of infection from monocyte-derived dendritic cells to CD4+ T cells were mediated by CCR5-dependent as well as DC-specific ICAM-3-grabbing nonintegrin-dependent pathways.