Biology subjects

Jetter, H.

Publications and source records attributed to Jetter, H..

3 recordsLinked to original sources

bioRxiv2026

A CRISPR/Cas9 screen reveals convergent dysregulation of neurological pathways within and across glycosylation pathways

Congenital disorders of glycosylation (CDG) are a broad group of disorders characterized by deficient glycosylation. CDG are caused by mutations in over 160 different genes regulating distinct steps and types of glycosylation. Despite the diversity of CDG-causing genes, patient phenotypes often overlap, with neurological symptoms present across many CDG. However, models to study conserved mechanisms underlying neurological dysfunction across CDG types are lacking. Therefore, we leveraged CRISPR/Cas9 to knockdown 15 glycosylation genes in zebrafish spanning 7 CDG classes. Through behavioral assays and in vivo imaging, we report changes in mobility, response to stimuli, and neuronal activity in many of our models. To uncover the molecular underpinnings of these phenotypes, we performed bulk-RNA sequencing on our models. We report differential expression in genes related to neurological development and function across all tested CDG classes, which will inform future hypothesis-driven studies defining new molecular targets for therapeutic intervention in CDG.

neuroscience↗

bioRxiv2026

Intellectual disability risk gene RFX4 regulates cortical neurogenesis by restraining neuronal differentiation

Despite the recent identification of RFX4 as a neurodevelopmental disorder risk gene, its role in cortical development remained unclear. Here, we identified both shared and lineage-specific RFX4 requirements for human cortical development using new human stem cell models of deficiency and pathogenic mutation. We found that RFX4 restrains neurogenesis by acting cooperatively with NOTCH signaling, specifically repressing pro-neuronal and synaptic gene expression in neural progenitors. We also determined that genome-wide binding of RFX3, another neurodevelopmental disorder risk gene, depends upon RFX4 to regulate synaptic gene expression. Furthermore, we identified lineage-specific functions for RFX4 in regulating proliferation during cortical inhibitory neuron development. Ultimately, we demonstrated that RFX4 deficiency persistently dysregulates neuronal gene expression through neuronal differentiation and disrupts cortical neuron stratification in organoid models. These consequences were absent in neurons generated by direct differentiation, confirming that neuronal phenotypes resulted from unconstrained neurogenesis. Finally, we modeled pathogenic missense mutation of the RFX4 DNA-binding domain. While this mutation strongly reduced DNA binding, it dysregulated synaptic gene expression distinctly from our deficiency models, supporting pathogenic mechanisms distinct from haploinsufficiency. Together, this work identified both shared and lineage-specific requirements for RFX4 during cortical development, building a necessary foundation for elucidating the etiology of RFX4-associated disorders.

developmental biology↗

bioRxiv2025

TBRS-associated DNMT3A mutations disrupt cortical interneuron differentiation and neuronal networks

Pathogenic mutations in DNMT3A cause Tatton-Brown-Rahman Syndrome (TBRS), a disorder characterized by somatic overgrowth of multiple tissues including the brain and intellectual disability (OGID). Here, we investigated TBRS etiology using new human pluripotent stem cell models, modeling varying levels of TBRS-associated loss of DNMT3A function. We identified lineage-specific overgrowth in TBRS ventral forebrain medial ganglionic eminence (MGE)-like progenitors, due in part to increased signaling through the PIK3/AKT/mTOR pathway that could be modulated to ameliorate this phenotype. By contrast, reduced DNA methylation during MGE-like progenitor differentiation into GABAergic interneurons caused premature expression of neuronal and synaptic genes, triggering precocious neuronal maturation. As a result, TBRS GABAergic neurons exhibited sufficient hyperactivity to alter the development and structure of neuronal networks, likely contributing to the intellectual disability and autism spectrum disorder common to TBRS patients. Together, this work elucidates new roles for DNMT3A-mediated gene repression in human cortical development, identifying critical requirements for regulating GABAergic neuron production and neuronal network function. These findings also support potential relationships between pathogenic mechanisms underlying TBRS and other OGIDs, including PIK3CA-related overgrowth syndrome and Weaver Syndrome, thus providing a foundation for future studies to identify common paradigms to treat these related disorders.

neuroscience↗