Baldwin, O. | bioRxiv Science

bioRxiv2025

Childhood brain tumours instruct cranial haematopoiesis and immunotolerance

Recent research has revealed a remarkable role for immunosurveillance in healthy and diseased brains, dispelling the notion that this organ is a passive immune-privileged site1-3. Better understanding of how this immunosurveillance operates could improve the treatment of neurological diseases. Here, using a novel genetically engineered mouse model of ZFTA-RELA ependymoma4-a childhood brain tumour-we characterised an immune circuit between the tumour and antigen presenting, haematopoietic stem/progenitor cells (HSPCs) in the skull bone marrow. The presentation of antigens in the cerebrospinal fluid (CSF) by HSPCs to CD4+ T cells, biased HSPC lineages toward myelopoiesis and polarised CD4+ T-cells to regulatory T cells (T- regs), culminating in tumour immunotolerance. Remarkably, a single infusion of antibodies directed against cytokines enriched in the CSF of mice bearing ZFTA-RELA ependymomas, choroid plexus carcinomas or Group-3 medulloblastoma-all aggressive childhood brain tumours-disrupted this process and caused profound tumour regression. These data unmask a mechanism by which skull bone marrow-derived HSPCs and CD4+ T cells cooperate to promote the immunotolerance of childhood brain tumours. Antibodies that disrupt this immunosurveillance could prove an effective therapy for these cancers that are less toxic than current treatments.

immunology↗

bioRxiv2024

Differential tissue deformability underlies shape divergence of the embryonic brain and spinal cord under fluid pressure

An expanded brain enables the complex behaviours of vertebrates that promote their adaptation in diverse ecological niches1-3. Initial morphological differences between the brain and spinal cord emerge as the antero-posteriorly patterned neural plate folds to form the neural tube4-7 during embryonic development. Following neural tube closure, a dramatic expansion of the brain diverges its shape from the spinal cord8, setting their distinct morphologies for further development9,10. How the brain and the spinal cord expand differentially remains unclear. Here, using the chicken embryo as a model, we show that the hindbrain expands through dorsal tissue thinning under a positive hydrostatic pressure from the neural tube lumen11,12 while the dorsal spinal cord shape resists the same pressure. Using magnetic droplets and atomic force microscopy, we reveal that the dorsal tissue in the hindbrain is more fluid than in the spinal cord. The dorsal hindbrain harbours more migratory neural crest cells13 and exhibits reduced apical actin and a disorganised laminin matrix compared to the dorsal spinal cord. Blocking the activity of neural crest-associated matrix metalloproteinases inhibited dorsal tissue thinning, leading to abnormal brain morphology. Transplanting early dorsal hindbrain cells to the spinal cord was sufficient to create a region with expanded brain-like morphology including a thinned-out roof. Our findings open new questions in vertebrate head evolution and neural tube defects, and suggest a general role of mechanical pre-pattern in creating shape differences in epithelial tubes.

developmental biology↗