Biology subjects

Kalish, B. T.

Publications and source records attributed to Kalish, B. T..

6 recordsLinked to original sources

bioRxiv2026

Maternal-fetal immune conflict contributes to male-specific impairments in a mouse model of neurodevelopmental disorders

Autism spectrum disorder (ASD) arises from genetic and environmental risk factors. One environmental factor, maternal immune activation (MIA)--in which pathogenic infection during pregnancy increases ASD risk in offspring--disproportionately affects males. However, the basis for this male-specific vulnerability, and the mechanisms by which inflammatory signals cross the maternal-fetal interface to affect the male embryo, remain largely unknown. Using the poly(I:C) mouse model of neurodevelopmental disorders, we characterize fetal, placental, and amniotic changes occurring within twenty-four hours of MIA. We find that 30% of embryos exhibit large-scale teratogenic abnormalities--ranging from decreased fetal weight to altered sensory organ development--while 70% develop normally. These abnormalities occur exclusively in a subset of males, never in females. Single-nucleus transcriptomics revealed robust induction of pro-inflammatory gene programs in the placentas of affected males across a broad range of cell types, and most prominently in spongiotrophoblasts--fetally derived cells that partly form the maternal-fetal border. These cells simultaneously down-regulate extracellular matrix and hormone biosynthesis pathways, coinciding with a breakdown in placental structural integrity and the accumulation of immune cells and cytokines in the amniotic fluid. One such cytokine, IL-6, is required for MIA-evoked developmental abnormalities to emerge. Our data indicate that MIA drives a rapid shift from an immunosuppressive to a pro-inflammatory maternal-fetal interface in a vulnerable subset of male embryos, producing acute, sex-restricted developmental deficits. We propose that male embryos may express unique proteins capable of triggering this inflammatory response, which--combined with MIA-induced loss of maternal immunosuppression--selectively derails male embryonic development.

developmental biology↗

bioRxiv2025

HuD controls widespread RNA stability to drive neuronal activity-dependent responses

Neuronal activity shapes brain development and refines synaptic connectivity in part through dynamic changes in gene expression. While activity-regulated transcriptional programs have been extensively characterized, the holistic effects of neuronal activity on the full RNA life cycle remain relatively unexplored. Here, we show that neuronal activity influences multiple stages of RNA metabolism in vitro and in vivo. Among these, RNA stability emerges as a previously underappreciated regulator of gene expression, exerting a stronger influence than transcription on total RNA levels for [~]15% of activity-dependent genes. We go on to profile 3'UTR mRNA motifs that are sufficient to modulate activity-dependent mRNA stability and employ machine learning to identify the neuronal-specific RNA-binding protein HuD as a key regulator of activity-dependent mRNA stabilization. We demonstrate that HuD shapes activity-dependent mRNA abundance of hundreds of transcripts in both soma and distal neuronal processes and that neuronal activity drives the reorganization of HuD-interacting proteins, thereby stabilizing HuD-bound mRNAs and directing them into translationally active granules. Finally, we find that many variants associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders disrupt or promote aberrant activity-dependent changes in mRNA stability. These findings reveal mRNA stability as a widespread mechanism of stimulus-responsive gene regulation in neurons with direct implications for the understanding of neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Perinatal Brain Injury Triggers Niche-Specific Changes to Cellular Biogeography

Preterm infants are at risk for brain injury and neurodevelopmental impairment due, in part, to white matter injury following chronic hypoxia exposure. However, the precise molecular mechanisms by which perinatal hypoxia disrupts early neurodevelopment are poorly understood. Here, we constructed a brain-wide map of the regenerative response to newborn brain injury using high-resolution imaging-based spatial transcriptomics to analyze over 1.3 million cells in a mouse model of chronic neonatal hypoxia. Additionally, we developed a new method for inferring condition-associated differences in cell type spatial proximity, enabling the identification of niche-specific changes in cellular architecture. We observed hypoxia-associated changes in region-specific cell states, cell type composition, and spatial organization. Importantly, our analysis revealed mechanisms underlying reparative neurogenesis and gliogenesis, while also nominating pathways that may impede circuit rewiring following perinatal hypoxia. Altogether, our work provides a comprehensive description of the molecular response to newborn brain injury.

neuroscience↗

bioRxiv2023

Single-nucleus profiling identifies accelerated oligodendrocyte precursor cell senescence in a mouse model of Down Syndrome

Down Syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive disability. However, the mechanisms by which triplication of human chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus RNA and ATAC-seq analysis of the cortex. We identify cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discover enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We find that senescence is restricted to a subset of cortical OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescues cortical OPC proliferation, restores microglial homeostasis, and improves contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS.

neuroscience↗

bioRxiv2022

γ-Protocadherins control synapse formation and peripheral branching of touch sensory neurons

Light touch sensation begins with activation of low-threshold mechanoreceptor (LTMR) endings in the skin and propagation of their signals to the spinal cord and brainstem. We found that the clustered protocadherin gamma (Pcdhg) gene locus, which encodes 22 cell-surface homophilic binding proteins, is required in somatosensory neurons for normal behavioral reactivity to a range of tactile stimuli. Developmentally, distinct Pcdhg isoforms mediate LTMR synapse formation through neuron-neuron interactions and peripheral axonal branching through neuron-glia interactions. The Pcdhgc3 isoform mediates homophilic interactions between sensory axons and spinal cord neurons to promote synapse formation in vivo, and is sufficient to induce postsynaptic specializations in vitro. Moreover, loss of Pcdhgs and somatosensory synaptic inputs to the dorsal horn lead to fewer corticospinal synapses onto dorsal horn neurons. These findings reveal essential roles for Pcdhg isoform diversity in somatosensory neuron synapse formation, peripheral axonal branching, and step-wise assembly of central mechanosensory circuitry.

neuroscience↗

bioRxiv2021

Developmental Dynamics of RNA Translation in the Human Brain

The precise regulation of gene expression is fundamental to neurodevelopment, plasticity, and cognitive function. While several studies have deeply profiled mRNA dynamics in the developing human brain, there is a fundamental gap in our understanding of accompanying translational regulation. We perform ribosome profiling from more than 70 human prenatal and adult cortex samples across ontogeny and into adulthood, mapping translation events at nucleotide resolution. In addition to characterizing the translational regulation of annotated open reading frames (ORFs), we identify thousands of previously unknown translation events, including small open reading frames (sORFs) that give rise to human- and/or brain-specific microproteins, many of which we independently verify using size-selected proteomics. Ribosome profiling in stem cell-derived human neuronal cultures further corroborates these findings and shows that several neuronal activity-induced long non-coding RNAs (lncRNAs), including LINC00473, a primate-specific lncRNA implicated in depression, encode previously undescribed microproteins. Physicochemical analysis of these brain microproteinss identifies a large class harboring arginine-glycine-glycine (RGG) repeats as strong candidates for regulating RNA metabolism. Moreover, we find that, collectively, these previously unknown human brain sORFs are enriched for variants associated with schizophrenia. In addition to significantly expanding the translational landscape of the developing brain, this atlas will serve as a rich resource for the annotation and functional interrogation of thousands of previously unknown brain-specific protein products.

neuroscience↗