Cell-type-specific roles of FOXP1 in the excitatory neuronal lineage during early neocortical murine development.

Forkhead box protein P1 (FOXP1), a transcription factor enriched in the neocortex, is associated with autism spectrum disorders (ASDs) and FOXP1 syndrome. Emx1;Foxp1 conditional deletion (Foxp1 conditional knockout [cKO]) in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers. However, the developmental and cell-type-specific mechanisms underlying these changes remained unclear.

Resilience to Endoplasmic Reticulum Stress Mitigates Calcium-Dependent Membrane Hyperexcitability Underlying Late Disease Onset in SCA6.

Unlabelled: An enduring puzzle in many inherited neurological disorders is the late onset of symptoms despite expression of function-impairing mutant protein early in life. We examined the basis for onset of impairment in Spinocerebellar ataxia type 6 (SCA6), a canonical late-onset neurodegenerative ataxia which results from a polyglutamine expansion in the voltage gated calcium channel, Cav2.1.

Sleep need driven oscillation of glutamate synaptic phenotype.

Sleep loss increases AMPA-synaptic strength and number in the neocortex. However, this is only part of the synaptic sleep loss response. We report an increased AMPA/NMDA EPSC ratio in frontal-cortical pyramidal neurons of layers 2-3.

Implementation and validation of single-cell genomics experiments in neuroscience.

Single-cell or single-nucleus transcriptomics is a powerful tool for identifying cell types and cell states. However, hypotheses derived from these assays, including gene expression information, require validation, and their functional relevance needs to be established. The choice of validation depends on numerous factors.

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.

Evolutionary neurogenomics at single-cell resolution.

The human brain is composed of increasingly recognized heterogeneous cell types. Applying single-cell genomics to brain tissue can elucidate relative cell type proportions as well as differential gene expression and regulation among humans and other species. Here, we review recent studies that utilized high-throughput genomics approaches to compare brains among species at single-cell resolution.

Cell type specific roles of FOXP1 during early neocortical murine development.

Cortical development is a tightly controlled process and any deviation during development may increase the susceptibility to neurodevelopmental disorders, such as autism spectrum disorders (ASD). Numerous studies identified mutations in , a transcription factor enriched in the neocortex, as causal for ASD and FOXP1 syndrome. Our group has shown that deletion in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers.

Compensation between FOXP transcription factors maintains proper striatal function.

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors Foxp1 and Foxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs.

FOXP1 regulates the development of excitatory synaptic inputs onto striatal neurons and induces phenotypic reversal with reinstatement.

Long-range glutamatergic inputs originating from the cortex and thalamus are indispensable for striatal development, providing the foundation for motor and cognitive functions. Despite their significance, transcriptional regulation governing these inputs remains largely unknown. We investigated the role of a transcription factor encoded by a high-risk autism-associated gene, , in sculpting glutamatergic inputs onto spiny projection neurons (SPNs) within the striatum.

Sleep need driven oscillation of glutamate synaptic phenotype.

Sleep loss increases AMPA-synaptic strength and number in the neocortex. However, this is only part of the synaptic sleep loss response. We report increased AMPA/NMDA EPSC ratio in frontal-cortical pyramidal neurons of layers 2-3.

FOXP1 regulates the development of excitatory synaptic inputs onto striatal neurons and induces phenotypic reversal with reinstatement.

Long-range glutamatergic inputs from the cortex and thalamus are critical for motor and cognitive processing in the striatum. Transcription factors that orchestrate the development of these inputs are largely unknown. We investigated the role of a transcription factor and high-risk autism-associated gene, FOXP1, in the development of glutamatergic inputs onto spiny projection neurons (SPNs) in the striatum.

Functional genomics and systems biology in human neuroscience.

Neuroscience research has entered a phase of key discoveries in the realm of neurogenomics owing to strong financial and intellectual support for resource building and tool development. The previous challenge of tissue heterogeneity has been met with the application of techniques that can profile individual cells at scale. Moreover, the ability to perturb genes, gene regulatory elements and neuronal activity in a cell-type-specific manner has been integrated with gene expression studies to uncover the functional underpinnings of the genome at a systems level.

Decoding DNA sequence-driven evolution of the human brain epigenome at cellular resolution.

DNA-based evolutionary comparisons of regulatory genomic elements enable insight into functional changes, overcoming tissue inaccessibility. Here, we harnessed adult and fetal cortex single-cell ATAC-seq datasets to uncover DNA substitutions specific to the human and human-ancestral lineages within apes. We found that fetal microglia identity is evolutionarily divergent in all lineages, whereas other cell types are conserved.

FOXP1 orchestrates neurogenesis in human cortical basal radial glial cells.

During cortical development, human basal radial glial cells (bRGCs) are highly capable of sustained self-renewal and neurogenesis. Selective pressures on this cell type may have contributed to the evolution of the human neocortex, leading to an increase in cortical size. bRGCs have enriched expression for Forkhead Box P1 (FOXP1), a transcription factor implicated in neurodevelopmental disorders (NDDs) such as autism spectrum disorder.

Molecular features driving cellular complexity of human brain evolution.

Human-specific genomic changes contribute to the unique functionalities of the human brain. The cellular heterogeneity of the human brain and the complex regulation of gene expression highlight the need to characterize human-specific molecular features at cellular resolution. Here we analysed single-nucleus RNA-sequencing and single-nucleus assay for transposase-accessible chromatin with sequencing datasets for human, chimpanzee and rhesus macaque brain tissue from posterior cingulate cortex.

Compensation between FOXP transcription factors maintains proper striatal function.

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factors and , which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs.

A single-cell trajectory atlas of striatal development.

The striatum integrates dense neuromodulatory inputs from many brain regions to coordinate complex behaviors. This integration relies on the coordinated responses from distinct striatal cell types. While previous studies have characterized the cellular and molecular composition of the striatum using single-cell RNA-sequencing at distinct developmental timepoints, the molecular changes spanning embryonic through postnatal development at the single-cell level have not been examined.

Gene Expression Analysis of Laser-Captured Purkinje Cells in the Essential Tremor Cerebellum.

Essential tremor (ET) is a common, progressive neurological disease characterized by an 8-12-Hz kinetic tremor. Despite its high prevalence, the patho-mechanisms of tremor in ET are not fully known. Through comprehensive studies in postmortem brains, we identified major morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs), suggesting that PC damage is central to ET pathogenesis.

Neuronal ambient RNA contamination causes misinterpreted and masked cell types in brain single-nuclei datasets.

Ambient RNA contamination in single-cell and single-nuclei RNA sequencing (snRNA-seq) is a significant problem, but its consequences are poorly understood. Here, we show that ambient RNAs in brain snRNA-seq datasets have a nuclear or non-nuclear origin with distinct gene set signatures. Both ambient RNA signatures are predominantly neuronal, and we find that some previously annotated neuronal cell types are distinguished by ambient RNA contamination.

Riding brain "waves" to identify human memory genes.

While there is extensive research on memory-related oscillations and brain gene expression, the relationship between oscillations and gene expression has rarely been studied. Recently, progress has been made to identify specific genes associated with oscillations that are correlated with episodic memory. Neocortical regions, in particular the temporal pole, have been examined in this line of research due to their accessibility during neurosurgical procedures.

Corticogenesis across species at single-cell resolution.

The neocortex (or pallium) consists of diverse cell types that are organized in a highly species-specific manner under strict spatiotemporal control during development. Many of the cell types are present transiently throughout development but contribute to permanent species-specific cortical features that are acquired through evolution. Therefore, capturing cell type-specific biological information has always been an important quest in the field of neurodevelopment.