Biology subjects

Neil, J. E.

Publications and source records attributed to Neil, J. E..

3 recordsLinked to original sources

bioRxiv2026

Pannexin-1 channel activity regulates neurogenesis and cell survival in the developing cortex

Mutations in genes encoding a range of ion-conducting proteins disrupt development of the cerebral cortex in humans, often causing polymicrogyria (PMG); yet how ion conduction guides the development of cortical architecture is not clear. Here, we describe three individuals with brain malformations including PMG and microcephaly in whom de novo, missense mutations were identified in PANX1--encoding an ATP and ion conducting channel. We show that these PMG-associated PANX1 mutations (p.D14H, p.M37R, and p.N338T) disrupt normal glycosylation and confer gain-of-function with respect to ATP release and channel conductance. In vivo modeling of mutant PANX1 in cortical progenitor cells demonstrated disrupted cell migration and excess cell death in both mice and ferret models. In vitro modeling of the p.N338T allele in human induced pluripotent stem cell (hiPSC)-derived neurons further revealed changes in neuronal morphology and increased excitability, and dysregulation of key transcription factors critical for neurogenesis and cell fate. In addition, p.N338T iPSC-derived neural progenitor cells displayed increased PANX1 activation. Our results show that normal PANX1 function contributes to cortical structure through regulation of ion conductance and ATP release and provides insight into how these processes influence corticogenesis and cytoarchitecture more broadly.

neuroscience↗

bioRxiv2024

Spatial Single-cell Analysis Decodes Cortical Layer and Area Specification

The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens of functionally specialized areas1,2. The layers and areas are distinguished both molecularly, by diverse neuronal and glial cell subtypes, and structurally, through intricate spatial organization3,4. While single-cell transcriptomics studies have advanced molecular characterization of human cortical development, a critical gap exists due to the loss of spatial context during cell dissociation5,6,7,8. Here, we utilized multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based cell segmentation, to examine the molecular, cellular, and cytoarchitectural development of human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing 16 million single cells, spans eight cortical areas across four time points in the second and third trimesters. We uncovered an early establishment of the six-layer structure, identifiable in the laminar distribution of excitatory neuronal subtypes by mid-gestation, long before the emergence of cytoarchitectural layers. Notably, while anterior-posterior gradients of neuronal subtypes were generally observed in most cortical areas, a striking exception was the sharp molecular border between primary (V1) and secondary visual cortices (V2) at gestational week 20. Here we discovered an abrupt binary shift in neuronal subtype specification at the earliest stages, challenging the notion that continuous morphogen gradients dictate mid-gestation cortical arealization6,10. Moreover, integrating single-nuclei RNA-sequencing and in situ whole transcriptomics revealed an early upregulation of synaptogenesis in V1-specific Layer 4 neurons, suggesting a role of synaptogenesis in this discrete border formation. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This work not only provides a valuable resource for the field, but also establishes a spatially resolved single-cell analysis paradigm that paves the way for a comprehensive developmental atlas of the human brain.

neuroscience↗

bioRxiv2023

Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations

Although mutations in many genes cause familial amyotrophic lateral sclerosis and frontotemporal dementia, most cases are sporadic (sALS and sFTD) with unclear etiology. We tested whether somatic mutations contribute to sALS and sFTD by deep targeted sequencing of 88 neurodegeneration-related genes in postmortem brain and spinal cord samples from 399 sporadic cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were observed in 2.1% of sporadic cases lacking deleterious germline variants. These variants occurred at very low allele fractions (typically <2%) and were often focal and enriched in disease-affected regions. Analysis of bulk RNA-seq data from an additional cohort identified deleterious somatic variants in DYNC1H1 and LMNA, genes associated with pediatric motor neuron degeneration. Targeted long-read sequencing further identified one sFTD case with de novo somatic C9orf72 repeat expansions. Together, these findings suggest that rare, focal somatic variants can contribute to sALS and sFTD and drive widespread neurodegeneration.

genetics↗