Biology subjects

Lanjewar, S. N.

Publications and source records attributed to Lanjewar, S. N..

3 recordsLinked to original sources

bioRxiv2025

Lead (Pb) exposure alters neural cell fate in the developing human brain

The heavy metal lead (Pb) is a developmental neurotoxicant associated with cognitive and behavioral deficits, but the cellular mechanisms underlying these impairments remain unclear. Here we show that prenatal Pb exposure biases human radial glia fate, prolonging neurogenesis and suppressing astrogenesis. We used hiPSC-derived cortical organoids, primary human fetal tissue, and in vivo xenografts to demonstrate that Pb exposure alters radial glial differentiation. Pb-exposed organoids contain a higher proportion of neurons and fewer astrocytes. We validated this differentiation bias in primary radial glia from human cortices (GW16-20), observing Pb-associated reductions in astrocyte commitment via genetic lineage tracing. This correlated with increased H3K27me3, a repressive histone modification deposited by the histone methyltransferase complex PRC2, suggesting epigenetic reprogramming as a mechanistic link between Pb and neural cell fate commitment. Our findings indicate that prenatal Pb exposure impacts lineage commitment in the developing brain, which may contribute to cognitive and behavioral impairment.

neuroscience↗

bioRxiv2024

ScISOr-ATAC reveals convergent and divergent splicing and chromatin specificities between matched cell types across cortical regions, evolution, and in Alzheimer's disease.

Multimodal measurements have become widespread in genomics, however measuring open chromatin accessibility and splicing simultaneously in frozen brain tissues remains unconquered. Hence, we devised Single-Cell-ISOform-RNA sequencing coupled with the Assay-for-Transposase-Accessible-Chromatin (ScISOr-ATAC). We utilized ScISOr-ATAC to assess whether chromatin and splicing alterations in the brain convergently affect the same cell types or divergently different ones. We applied ScISOr-ATAC to three major conditions: comparing (i) the Rhesus macaque (Macaca mulatta) prefrontal cortex (PFC) and visual cortex (VIS), (ii) cross species divergence of Rhesus macaque versus human PFC, as well as (iii) dysregulation in Alzheimers disease in human PFC. We found that among cortical-layer biased excitatory neuron subtypes, splicing is highly brain-region specific for L3-5/L6 IT_RORB neurons, moderately specific in L2-3 IT_CUX2.RORB neurons and unspecific in L2-3 IT_CUX2 neurons. In contrast, at the chromatin level, L2-3 IT_CUX2.RORB neurons show the highest brain-region specificity compared to other subtypes. Likewise, when comparing human and macaque PFC, strong evolutionary divergence on one molecular modality does not necessarily imply strong such divergence on another molecular level in the same cell type. Finally, in Alzheimers disease, oligodendrocytes show convergently high dysregulation in both chromatin and splicing. However, chromatin and splicing dysregulation most strongly affect distinct oligodendrocyte subtypes. Overall, these results indicate that chromatin and splicing can show convergent or divergent results depending on the performed comparison, justifying the need for their concurrent measurement to investigate complex systems. Taken together, ScISOr-ATAC allows for the characterization of single-cell splicing and chromatin patterns and the comparison of sample groups in frozen brain samples.

genomics↗

bioRxiv2022

Computational Identification of Ligand-Receptor Pairs that Drive Human Astrocyte Development

Extrinsic signaling between diverse cell types is crucial to nervous system development. Ligand binding is a key driver of developmental processes, but it remains a significant challenge to disentangle how collections of these signals act cooperatively to affect changes in recipient cells. In the developing human brain, cortical progenitors transition from neurogenesis to gliogenesis in a stereotyped progression that is influenced by extrinsic ligands. Therefore, we sought to use the wealth of published genomic data in the developing human brain to identify and then test novel ligand combinations that act synergistically to drive gliogenesis. Using computational tools, we identified ligand-receptor pairs that are expressed at appropriate developmental stages, in relevant cell types, and whose activation is predicted to cooperatively stimulate complimentary astrocyte gene signatures. We then tested a group of five neuronally-secreted ligands and validated their synergistic contributions to astrocyte development within both human cortical organoids and primary fetal tissue. We confirm cooperative capabilities of these ligands far greater than their individual capacities and discovered that their combinatorial effects converge on AKT/mTOR signaling to drive transcriptomic and morphological features of astrocyte development. This platform provides a powerful agnostic framework to identify and test how extrinsic signals work in concert to drive developmental processes. HIGHLIGHTSO_LIComputational prediction of active ligand-receptor pairs in the developing brain C_LIO_LISynergistic contributions of predicted ligands drive astrocyte development C_LIO_LILigands induce transcriptomic and morphological features of mature astrocytes C_LIO_LICooperative ligand activity converges on AKT/mTOR signaling C_LI

neuroscience↗