Biology subjects

Moyer, C.

Publications and source records attributed to Moyer, C..

4 recordsLinked to original sources

bioRxiv2025

Persistent cortical excitatory neuron dysregulation in adult Chd8 haploinsufficient mice.

CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/-mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/-mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.

genomics↗

bioRxiv2023

Translational modulation by ISRIB alleviates synaptic and behavioral phenotypes in Fragile X syndrome

Fragile X syndrome (FXS) is caused by the functional loss of Fragile X messenger ribonucleoprotein (FMRP), a translational regulator that binds the transcripts of many proteins involved in synaptic function and plasticity. Dysregulated protein synthesis is a central effect of FMRP loss and to date direct translational modulation has not been leveraged in the treatment of FXS. Thus, we examined the effect of the small molecule translational modulator, Integrated Stress Response Inhibitor (ISRIB), in treating synaptic and behavioral symptoms of FXS. Using a combination of population-level single synapse analysis, in vivo two-photon microscopy, and behavioral analysis, we revealed a mechanism for the appearance of dense and immature dendritic spines, which are observed in human FXS patients and Fmr1 knockout (KO) mice. Our data suggest that FMRP loss at the synapse dysregulates synaptic protein abundance and that spines are disproportionately stabilized through increased PSD-95 expression but prevented from maturing through reduced synaptic accumulation of glutamate receptors. ISRIB rescues these molecular and synaptic deficits in FXS and improves social recognition in Fmr1 KO mice. These findings highlight the therapeutic potential of targeting core translational mechanisms and the differential impact of FMRP on synaptic and cellular function in FXS and neurodevelopmental disorders more broadly.

neuroscience↗

bioRxiv2022

Inferring gene expression models from snapshot RNA data

1Gene networks, key toward understanding a cells regulatory response, underlie experimental observations of single cell transcriptional dynamics. While information on the gene network is encoded in RNA expression data, existing computational frameworks cannot currently infer gene networks from such data. Rather, gene networks--composed of gene states, their connectivities, and associated parameters--are currently deduced by pre-specifying gene state numbers and connectivity prior to learning associated rate parameters. As such, the correctness of gene networks cannot be independently assessed which can lead to strong biases. By contrast, here we propose a method to learn full distributions over gene states, state connectivities, and associated rate parameters, simultaneously and self-consistently from single molecule level RNA counts. Notably, our method propagates noise originating from fluctuating RNA counts over networks warranted by the data by treating networks themselves as random variables. We achieve this by operating within a Bayesian nonparametric paradigm. We demonstrate our method on the lacZ pathway in Escherichia coli cells, the STL1 pathway in Saccharomyces cerevisiae yeast cells, and verify its robustness on synthetic data.

biophysics↗

bioRxiv2018

Humoral immune response to adenovirus induce tolerogenic bystander dendritic cells that promote generation of regulatory T cells

Following repeated encounters with adenoviruses most of us develop robust humoral and cellular immune responses that are thought to act together to combat ongoing and subsequent infections. Yet in spite of robust immune responses, adenoviruses establish subclinical persistent infections that can last for decades. While adenovirus persistence pose minimal risk in B-cell compromised individuals, if T-cell immunity is severely compromised, reactivation of latent adenoviruses can be life threatening. This dichotomy led us to ask how anti-adenovirus antibodies influence adenovirus-specific T-cell immunity. Using primary human blood cells, transcriptome and secretome profiling, and pharmacological, biochemical, genetic, molecular, and cell biological approaches, we initially found that healthy adults harbor adenovirus-specific regulatory T cells (Tregs). As peripherally induced Tregs are generated by tolerogenic dendritic cells (DCs), we then addressed how tolerogenic DCs could be created. Here, we demonstrate that DCs that take up immunoglobulin-complexed (IC)-adenoviruses create an environment that causes bystander DCs to become tolerogenic. These adenovirus antigen-loaded tolerogenic DCs can drive naive T cells to mature into adenovirus-specific Tregs. Our results may provide ways to improve antiviral therapy and/or pre-screening high-risk individuals undergoing immunosuppression.\n\nAuthor summaryWhile numerous studies have addressed the cellular and humoral response to primary virus encounters, relatively little is known about the interplay between persistent infections, neutralizing antibodies, antigen-presenting cells, and the T-cell response. Our studies suggests that if adenovirus-antibody complexes are taken up by professional antigen-presenting cells (dendritic cells), the DCs generate an environment that causes bystander dendritic cells to become tolerogenic. These tolerogenic dendritic cells favors the creation of adenovirus-specific regulatory T cells. While this pathway likely favors pathogen survival, there may be advantages for the host also.

microbiology↗