Alexis English Ivec

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• Glioma synapses recruit mechanisms of adaptive plasticity. Nature Taylor, K. R., Barron, T., Hui, A., Spitzer, A., Yalcin, B., Ivec, A. E., Geraghty, A. C., Hartmann, G. G., Arzt, M., Gillespie, S. M., Kim, Y. S., Maleki Jahan, S., Zhang, H., Shamardani, K., Su, M., Ni, L., Du, P. P., Woo, P. J., Silva-Torres, A., Venkatesh, H. S., Mancusi, R., Ponnuswami, A., Mulinyawe, S., Keough, M. B., Chau, I., Aziz-Bose, R., Tirosh, I., Suva, M. L., Monje, M. 2023

  Abstract

  The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.

  View details for DOI 10.1038/s41586-023-06678-1

  View details for PubMedID 37914930

• Multipotent progenitors instruct ontogeny of the superior colliculus. Neuron Cheung, G., Pauler, F. M., Koppensteiner, P., Krausgruber, T., Streicher, C., Schrammel, M., Gutmann-Özgen, N., Ivec, A. E., Bock, C., Shigemoto, R., Hippenmeyer, S. 2023

  Abstract

  The superior colliculus (SC) in the mammalian midbrain is essential for multisensory integration and is composed of a rich diversity of excitatory and inhibitory neurons and glia. However, the developmental principles directing the generation of SC cell-type diversity are not understood. Here, we pursued systematic cell lineage tracing in silico and in vivo, preserving full spatial information, using genetic mosaic analysis with double markers (MADM)-based clonal analysis with single-cell sequencing (MADM-CloneSeq). The analysis of clonally related cell lineages revealed that radial glial progenitors (RGPs) in SC are exceptionally multipotent. Individual resident RGPs have the capacity to produce all excitatory and inhibitory SC neuron types, even at the stage of terminal division. While individual clonal units show no pre-defined cellular composition, the establishment of appropriate relative proportions of distinct neuronal types occurs in a PTEN-dependent manner. Collectively, our findings provide an inaugural framework at the single-RGP/-cell level of the mammalian SC ontogeny.

  View details for DOI 10.1016/j.neuron.2023.11.009

  View details for PubMedID 38096816

• Durable CRISPR-Based Epigenetic Silencing BioDesign Research Nakamura, M., Ivec, A. E., Gao, Y., Qi, L. S. 2021: 8

  View details for DOI 10.34133/2021/9815820