Biology subjects

Ding, J. W.

Publications and source records attributed to Ding, J. W..

4 recordsLinked to original sources

bioRxiv2026

Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD

Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.

neuroscience↗

bioRxiv2025

ANTIPODE Provides a Global View of Cell Type Homology and Transcriptomic Divergence in the Developing Mammalian Brain

Diverse neurons and glia are generated in conserved spatial and temporal sequences during mammalian brain development. Divergence in gene regulatory networks can alter brain composition, scaling, timing, and function. However, resolving the identity, extent, and principles of gene regulatory divergence requires cellular-resolution surveys spanning brain regions and species and improved methods for defining cell type homologies. Here, we present ANTIPODE, a deep-learning variational inference framework that simultaneously integrates single-cell datasets, identifies homologous cell types, and parcellates differential expression across cell types, modules, and covariance. Applying ANTIPODE to a census of the whole developing macaque brain and a meta-atlas of human, macaque, and mouse brain development, we find broad conservation of initial neuron classes but widespread regulatory divergence within homologous types, shaped by genomic context, cell lineage, and developmental timing. Together, ANTIPODE provides a formalized and interpretable framework for cross-species single-cell analysis and reveals principles of gene regulatory divergence in mammalian brain evolution.

developmental biology↗

bioRxiv2025

Accelerated Tempo of Cortical Neurogenesis in Down Syndrome

Down syndrome (DS), caused by trisomy 21 (TS21), is the most common genetic cause of intellectual disability1,2. The neurological impacts of DS first manifest during prenatal development through reduced radial glia (RG) neural stem cell proliferation, reduced cortical volume and imbalanced cortical cell types3-6. However, the developmental mechanisms underlying altered cortical neurogenesis in DS remain elusive. Here we show by high-throughput lineage tracing in organotypic culture that TS21 accelerates RG lineage progression, driving premature production of cortical inhibitory neurons (INs) and oligodendrocytes. Somatic lineage coupling connects dysregulated neurogenic tempo to altered cellular composition in the adult DS brain. Finally, lineage-resolved differential expression reveals elevated interferon responses specifically in RG biased to producing INs. Together, our findings link TS21 genomic abnormalities to candidate molecular pathways and developmental mechanisms altering the cellular landscape in DS with therapeutic relevance.

developmental biology↗

bioRxiv2025

Dissecting Gene Regulatory Networks Governing Human Cortical Cell Fate

Human cortical neurogenesis involves conserved and specialized developmental processes during a restricted window of prenatal development. Radial glia (RG) neural stem cells shape cortical cell diversity by giving rise to excitatory neurons, oligodendrocytes, and astrocytes, as well as olfactory bulb interneurons (INs) and a recently characterized population of cortical INs1,2. Complex genetic programs orchestrated by transcription factor (TF) circuits govern the balance between self-renewal and differentiation, and between different cell fates3-8. Despite progress in measuring gene regulatory network activity during human cortical development9-12, functional studies are required to evaluate the roles of TFs and effector genes in human RG lineage progression. Here we establish a human primary culture system that allows sensitive discrimination of cell fate dynamics and apply single cell clustered regularly interspaced short palindromic repeats interference (CRISPRi) screening13,14 to examine the transcriptional and cell fate consequences of 44 TFs active during cortical neurogenesis. We identified multiple TFs, with novel roles in cortical neurogenesis, including ZNF219, previously uncharacterized, that represses neural differentiation and NR2E1 and ARX that have opposing roles in regulating RG lineage plasticity and progression across developmental stages. We also uncovered convergent effector genes downstream of multiple TFs enriched in neurodevelopmental and neuropsychiatric disorders and observed conserved mechanisms of RG lineage plasticity across primates. We further uncovered a postmitotic role for ARX in safeguarding IN subtype specification through repressing LMO1. Our study provides a framework for dissecting regulatory networks driving cell fate consequences during human neurogenesis.

developmental biology↗