Opportunities and challenges of single-cell and spatially resolved genomics methods for neuroscience discovery.

Over the past decade, single-cell genomics technologies have allowed scalable profiling of cell-type-specific features, which has substantially increased our ability to study cellular diversity and transcriptional programs in heterogeneous tissues. Yet our understanding of mechanisms of gene regulation or the rules that govern interactions between cell types is still limited. The advent of new computational pipelines and technologies, such as single-cell epigenomics and spatially resolved transcriptomics, has created opportunities to explore two new axes of biological variation: cell-intrinsic regulation of cell states and expression programs and interactions between cells.

Specialized structure and function of the apical extracellular matrix at sense organs.

Apical extracellular matrix (aECM) covers every surface of the body and exhibits tissue-specific structures that carry out specialized functions. This is particularly striking at sense organs, where aECM forms the interface between sensory neurons and the environment, and thus plays critical roles in how sensory stimuli are received. Here, we review the extraordinary adaptations of aECM across sense organs and discuss how differences in protein composition and matrix structure assist in sensing mechanical forces (tactile hairs, campaniform sensilla, and the tectorial membrane of the cochlea); tastes and smells (uniporous gustatory sensilla and multiporous olfactory sensilla in insects, and salivary and olfactory mucus in vertebrates); and light (cuticle-derived lenses in arthropods and mollusks).

Dendrite morphogenesis in Caenorhabditis elegans.

Since the days of Ramón y Cajal, the vast diversity of neuronal and particularly dendrite morphology has been used to catalog neurons into different classes. Dendrite morphology varies greatly and reflects the different functions performed by different types of neurons. Significant progress has been made in our understanding of how dendrites form and the molecular factors and forces that shape these often elaborately sculpted structures.

TDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression.

TAR DNA-binding protein 43 (TDP-43) proteinopathy in brain cells is the hallmark of amyotrophic lateral sclerosis (ALS) but its cause remains elusive. Asparaginase-like-1 protein (ASRGL1) cleaves isoaspartates, which alter protein folding and susceptibility to proteolysis. ASRGL1 gene harbors a copy of the human endogenous retrovirus HML-2, whose overexpression contributes to ALS pathogenesis.

Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity.

SAX-7/L1CAM acts with the adherens junction proteins MAGI-1, HMR-1/Cadherin, and AFD-1/Afadin to promote glial-mediated dendrite extension.

Adherens junctions (AJs) are a fundamental organizing structure for multicellular life. Although AJs are studied mainly in epithelia, their core function - stabilizing cell contacts by coupling adhesion molecules to the cytoskeleton - is important in diverse tissues. We find that two sensory neurons, URX and BAG, require conserved AJ proteins for dendrite morphogenesis.

A sex-specific switch in a single glial cell patterns the apical extracellular matrix.

Apical extracellular matrix (aECM) constitutes the interface between every tissue and the outside world. It is patterned into diverse tissue-specific structures through unknown mechanisms. Here, we show that a male-specific genetic switch in a single C.

Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution.

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components.

Safety and Tolerability of Whole Soybean Products: A Dose-Escalating Clinical Trial in Older Adults with Obesity.

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70-85 years) with obesity.

Results of a phase Ib study of SB-121, an investigational probiotic formulation, a randomized controlled trial in participants with autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by core impairments in social communication as well as restricted, repetitive patterns of behavior and/or interests. Individuals with ASD, which includes about 2% of the US population, have challenges with activities of daily living and suffer from comorbid medical and mental health concerns. There are no drugs indicated for the core impairments of ASD.

A sex-specific switch in a single glial cell patterns the apical extracellular matrix.

Apical extracellular matrix (aECM) constitutes the interface between every tissue and the outside world. It is patterned into diverse tissue-specific structures through unknown mechanisms. Here, we show that a male-specific genetic switch in a single glial cell patterns the aECM into a ∼200 nm pore, allowing a male sensory neuron to access the environment.

Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington's disease.

Striatal projection neurons (SPNs), which progressively degenerate in human patients with Huntington's disease (HD), are classified along two axes: the canonical direct-indirect pathway division and the striosome-matrix compartmentation. It is well established that the indirect-pathway SPNs are susceptible to neurodegeneration and transcriptomic disturbances, but less is known about how the striosome-matrix axis is compromised in HD in relation to the canonical axis. Here we show, using single-nucleus RNA-sequencing data from male Grade 1 HD patient post-mortem brain samples and male zQ175 and R6/2 mouse models, that the two axes are multiplexed and differentially compromised in HD.

A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane.

Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface.

When is a neuron like an epithelial cell.

Neurons and epithelia are viewed as fundamentally different cell types, yet some sensory neurons exhibit hallmarks of epithelial cells. For example, they use tight junctions to form a diffusion barrier continuous with the skin or other epithelia and they exhibit bona fide apical-basal polarity, with an outward-facing apical surface that is biochemically and functionally distinct from their inward-facing basolateral surface. Yet they are unmistakeably neurons with axon-dendrite polarity.

Back-to-BACs in Huntington's disease modeling.

In this issue of Neuron, Gu et al. (2022) describe a new BAC mouse model that faithfully recapitulates various aspects of Huntington's disease pathobiology and reveals important insights into the relative toxicities of mHTT-derived products.

Axon-dendrite and apical-basolateral sorting in a single neuron.

Cells are highly organized machines with functionally specialized compartments. For example, membrane proteins are localized to axons or dendrites in neurons and to apical or basolateral surfaces in epithelial cells. Interestingly, many sensory cells-including vertebrate photoreceptors and olfactory neurons-exhibit both neuronal and epithelial features.

Single-cell dissection of the human brain vasculature.

Despite the importance of the cerebrovasculature in maintaining normal brain physiology and in understanding neurodegeneration and drug delivery to the central nervous system, human cerebrovascular cells remain poorly characterized owing to their sparsity and dispersion. Here we perform single-cell characterization of the human cerebrovasculature using both ex vivo fresh tissue experimental enrichment and post mortem in silico sorting of human cortical tissue samples. We capture 16,681 cerebrovascular nuclei across 11 subtypes, including endothelial cells, mural cells and three distinct subtypes of perivascular fibroblast along the vasculature.

Loss of the Extracellular Matrix Protein DIG-1 Causes Glial Fragmentation, Dendrite Breakage, and Dendrite Extension Defects.

The extracellular matrix (ECM) guides and constrains the shape of the nervous system. In , DIG-1 is a giant ECM component that is required for fasciculation of sensory dendrites during development and for maintenance of axon positions throughout life. We identified four novel alleles of in three independent screens for mutants affecting disparate aspects of neuronal and glial morphogenesis.

Lineage-specific control of convergent differentiation by a Forkhead repressor.

During convergent differentiation, multiple developmental lineages produce a highly similar or identical cell type. However, few molecular players that drive convergent differentiation are known. Here, we show that the C.