Biology subjects

Ardekani, C.

Publications and source records attributed to Ardekani, C..

3 recordsLinked to original sources

bioRxiv2026

Precocious maturation and Purkinje cell dysfunction in the mouse Chd8 haploinsufficient cerebellum

The cerebellum plays an emerging, but understudied, role in neurodevelopmental disorders (NDDs). Mutations in CHD8 cause a monogenic NDD (CHD8-NDD) characterized by autism and other manifestations, and prior work in Chd8 mutant mice reported cerebellar abnormalities, raising the possibility of cerebellar contribution to CHD8-NDD. To comprehensively characterize the impact of Chd8 haploinsufficiency on cerebellar development and function, we profiled the postnatal day 12 (P12) cerebellum of germline Chd8+/- mice using transcriptomic, morphological, and electrophysiological approaches. Gross cerebellar morphology was unaffected, but single-nucleus RNA sequencing revealed transcriptomic signatures of pathophysiology across cell types, including accelerated maturation of molecular layer interneurons and granule cells, and altered myelination state of oligodendrocytes. Purkinje cells (PCs) showed the strongest transcriptomic burden of any cell type and, consistent with this, exhibited altered morphology and electrophysiological properties. Bulk RNA sequencing confirmed that transcriptomic pathology persists into adulthood, indicating lasting impacts on both neuronal and glial gene expression. Together, these results capture cell-type-specific cerebellar perturbations associated with Chd8 haploinsufficiency and support the cerebellum as a relevant site of pathology in CHD8-NDD.

neuroscience↗

bioRxiv2025

Molecular interactions of Chd8 in mouse brain highlights a role in chromatin-associated RNA processing

The chromatin remodeler CHD8 is a model risk gene for neurodevelopmental disorders (NDDs). While CHD8 has nucleosome remodeling capacity, evidence suggests it participates in processes beyond chromatin regulation, raising questions about function in the brain and role in NDDs. We defined CHD8 interactions using a comprehensive multimodal omics approach. Immunoprecipitation followed by mass spectrometry (IP-MS) identified a complex interaction network enriched for chromatin remodeling, RNA processing, and cytoskeletal proteins in neonatal mouse forebrain. We implemented CHD8-TurboID in HEK293T cells, validating IP-MS signatures and further identifying a role in mitosis. In addition to DNA, Chd8 complexed with RNA in mouse forebrain, with affinity for genes associated with RNA splicing and nervous system development and overlap between Chd8-bound mRNA and promoters. Finally, Chd8 interaction affinity with RNA splicing factors was reduced in Chd8 haploinsufficient mice. These findings expand understanding of CHD8 function and identify a dosage-sensitive NDD-relevant role in chromatin-associated RNA processing.

molecular biology↗

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↗