Biology subjects

Buecking, J.

Publications and source records attributed to Buecking, J..

2 recordsLinked to original sources

bioRxiv2026

Pervasive Somatic Mutations in NF1 Drive Cell Type and Spatially Specific Clonal Selection in Neurofibromatosis

Tumorigenesis is a multi-step process shaped by the accumulation of somatic driver mutations, but identifying the earliest steps and cell of origin of tumorigenesis remains challenging. Single cell genomics in >1.7 million single cells across donors with the cancer predisposition syndrome neurofibromatosis type 1 (NF-1), shows that somatic 'second-hit' mutations in NF1 are pervasive and show positive clonal selection in oligodendrocytes (OLs) and OL precursor cells (OPCs), but are exceedingly rare in neurons and other lineages. Combined spatial genotyping and transcriptomic analysis enabled dissection of cell autonomous and non-autonomous effects of second-hit mutations including clonal expansion of mutant OPCs with strong bias for cerebral gray matter versus white matter, suggesting that gray matter influences OPC proliferation and differentiation via non-cell autonomous interactions between OPCs and neurons. NF1-null OL lineage cells upregulate CDKN2A--a tumor suppressor frequently lost in NF1-mutant tumors--whereas brain cancers from these same individuals show CDKN2A loss across multiple cancer cell states, suggesting CDKN2A loss in OPCs is a critical step in tumor progression. Our findings reveal developmentally early, exquisitely lineage-specific NF1 somatic mutations in premalignant NF-1 brain, suggest cell autonomous and non-autonomous roles in clonal selection in brain, and suggest that clones harboring cancer driver mutations can persist over a lifetime in phenotypically normal tissues.

genetics↗

bioRxiv2026

Multi-omics profiling reveals MAGEL2-driven defects in human corticogenesis shared across Prader-Willi and Schaaf-Yang syndromes.

The human cortex acquires its advanced cognitive capacity through tightly regulated developmental programs, disruption of which underlies neurodevelopmental disorders such as Schaaf-Yang syndrome (SYS) and Prader-Willi syndrome (PWS). While SYS results from pathogenic variants in the imprinted gene MAGEL2, PWS arises from chromosomal deletions, imprinting defects or uniparental disomy encompassing the MAGEL2 locus. However, the contribution of MAGEL2 to disease pathogenesis and human corticogenesis is not fully understood. Here, we performed integrated transcriptomic, proteomic, and ubiquitinomic profiling of cortical neurons derived from CRISPR/Cas9-engineered isogenic human pluripotent stem cells (hiPSC) modeling SYS and PWS. Beyond PWS-specific signatures including dysregulated ribosomal processes, we identified MAGEL2-dependent defects shared across both disorders. These include reduced progenitor proliferation, accelerated neuronal maturation, impaired migration and adhesion, as well as abnormal synaptic development, collectively linking PWS and SYS at the level of cortical development. Notably, these phenotypes partially overlap with those observed in other neurodevelopmental disorders, suggesting that MAGEL2 governs core pathways broadly vulnerable in disease. Together, our findings establish MAGEL2 as a key regulator of human cortical development, provide a unifying mechanistic framework for SYS and PWS, accessible via a web-based platform.

neuroscience↗