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Biology subjects

Zonca, A.

Publications and source records attributed to Zonca, A..

2 recordsLinked to original sources

NeuRoDev resolves lifelong temporal and cellular variation in human cortical gene expression

Understanding how the human brain develops and functions requires direct analysis of human cells. Single-cell atlases open unprecedented opportunities to survey cell physiological molecular states as the brain develops. However, technical challenges limit their potential. We present NeuRoDev, a computational resource with highly curated transcriptomic data and novel analytical tools to investigate neuronal and glial development in the human cortex. NeuRoDev compresses [~]1M single-cell transcriptomes into integrative summary networks of reproducible cell clusters that capture temporal and cellular variation across all stages of human brain development. It provides a reference framework to directly interrogate cellular maturation dynamics, contextualize gene function, and interpret experimental organoid models. We use NeuRoDev to investigate developmental variation in cell physiology, reconstruct genesis and maturation dynamics in neuronal and glial cells, and interpret time-series data from organoid models. NeuRoDev is provided as a freely available software package and as web applications for interactive data analysis.

neuroscience↗

WWOX deficiency impairs neurogenesis and neuronal function in human organoids

WOREE and SCAR12 syndromes are rare neurodevelopmental disorders caused by WWOX mutations, severely impairing brain development. The pleiotropic nature of WWOX complicates identifying specific mechanisms. Using neural organoids and single-cell transcriptomics, we identified radial glial cells (RGs) as preferentially affected, with disrupted cell cycle dynamics leading to an accumulation of cells in the G2/M and S phases, overexpression of the proto-oncogene MYC, and concomitant reduction in neuronal generation. Patient-derived organoids exhibited milder phenotypes compared to knockout organoids, showing functional neuronal impairments like hyperexcitability and delayed differentiation rather than RG dysfunction. Remarkably, gene therapy restored neuronal function, normalizing hyperexcitability and promoting maturation, without disturbing RG populations. We propose a model in which WWOX mutations impair neurogenesis via RG through cell-type specific dysregulation of the MYC and Wnt signaling pathways. These insights highlight potential therapeutic strategies for WWOX-related disorders and open avenues for interventions targeting these key molecular pathways. TeaserWWOX mutations disrupt radial glial function and neurogenesis via MYC dysregulation, with gene therapy offering targeted restoration.

neuroscience↗