Biology subjects

Wallace, J. L.

Publications and source records attributed to Wallace, J. L..

5 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

Interrogating the Regulatory Function of HAQERs during Human Cortical Development

BackgroundSequence divergence within gene regulatory elements has been proposed to play an important role in the evolution of human-specific traits, including cortical expansion. However, the mutational processes that efficiently modify gene regulatory elements and the target genes upon which they act are poorly understood. We investigated the regulatory function and origins of the fastest evolved regions in the human genome, termed Human Ancestor Quickly Evolved Regions (HAQERs), in their native genomic context during human cerebral cortex development. ResultsWe identified 50 HAQERs with accessible chromatin in developing human cortex, largely arising from previously unconstrained ancestral sequences. To test the necessity of these HAQERs for gene regulation, we established an all-in-one CRISPRi lentiviral vector and linked 26 HAQERs to nearby target genes across cell types and Wnt pathway activation contexts. Rapid gains of CpGs distinguished HAQERs active during cortical development and displaying human-specific epigenomic marks. As a high density of CpG sites can drive formation of permissive chromatin, we identified 107 HAQERs with at least 17 human-specific CpG gains per kb, termed HAQER CpG Beacons. These HAQERs emerged via contributions from GC-biased gene conversion (gBGC) with evidence for selection preferentially fixing CpG sites. Notably, the CHL1 and DPP10 loci, both implicated in human neurological disorders, each harbored two gene-linked HAQER CpG Beacons. ConclusionsOur findings reveal HAQER target genes and support a model where gBGC and natural selection jointly drive regulatory-altering CpG variants to fixation, forging regulatory innovations in the human cortex.

evolutionary 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↗

bioRxiv2024

Interspecies Organoids Reveal Human-Specific Molecular Features of Dopaminergic Neuron Development and Vulnerability

The disproportionate expansion of telencephalic structures during human evolution involved tradeoffs that imposed greater connectivity and metabolic demands on midbrain dopaminergic neurons. Despite the central role of dopaminergic neurons in human-enriched disorders, molecular specializations associated with human-specific features and vulnerabilities of the dopaminergic system remain unexplored. Here, we establish a phylogeny-in-a-dish approach to examine gene regulatory evolution by differentiating pools of human, chimpanzee, orangutan, and macaque pluripotent stem cells into ventral midbrain organoids capable of forming long-range projections, spontaneous activity, and dopamine release. We identify human-specific gene expression changes related to axonal transport of mitochondria and reactive oxygen species buffering and candidate cis- and trans-regulatory mechanisms underlying gene expression divergence. Our findings are consistent with a model of evolved neuroprotection in response to tradeoffs related to brain expansion and could contribute to the discovery of therapeutic targets and strategies for treating disorders involving the dopaminergic system.

evolutionary biology↗

bioRxiv2019

Microglia are necessary for normal functional development of adult-born neurons in the olfactory bulb

Microglia play key roles in regulating synapse development and refinement in the developing brain, but it is unknown whether they are similarly involved during adult neurogenesis. By transiently ablating microglia from the healthy adult mouse brain, we show that microglia are necessary for the normal functional development of adult-born granule cells (abGCs) in the olfactory bulb. Microglia ablation reduces the odor responses of developing, but not preexisting GCs in vivo in both awake and anesthetized mice. Microglia preferentially target their motile processes to interact with mushroom spines on abGCs, and when microglia are absent, abGCs develop smaller spines and receive weaker excitatory synaptic inputs. These results suggest that microglia promote the development of excitatory synapses onto developing abGCs, which may impact the function of these cells in the olfactory circuit.

neuroscience↗