Keren-Shaul, H. | bioRxiv Science

bioRxiv2019

Transneuronal interactions facilitate axonal compartment formation

The mechanisms controlling wiring of neuronal networks are largely unknown. The stereotypic architecture of the Drosophila mushroom-body (MB) offers a unique system to study circuit assembly. The adult medial MB {gamma}-lobe is comprised of a long bundle of axons that wires with specific modulatory and output neurons in a tiled manner defining five distinct zones. We found that the immunoglobulin superfamily protein Dpr12 is cell-autonomously required in {gamma}-neurons for their developmental regrowth into the distal {gamma}4/5 zones, where both Dpr12 and its interacting protein, DIP-{delta}, are enriched. DIP-{delta} functions in a subset of dopaminergic neurons that wire with {gamma}-neurons within the {gamma}4/5 zone. During metamorphosis, these dopaminergic projections arrive to the {gamma}4/5 zone prior to {gamma}-axons, suggesting that {gamma}-axons extend through a prepatterned region. Thus, Dpr12/DIP-{delta} transneuronal interaction is required for {gamma}4/5 zone formation. Our study sheds light onto molecular and cellular mechanisms underlying circuit formation within subcellular resolution.

neuroscience↗

bioRxiv2019

Pan-cancer single cell RNA-seq uncovers recurring programs of cellular heterogeneity

Cultured cell lines are the workhorse of cancer research, but it is unclear to what extent they recapitulate the cellular heterogeneity observed among malignant cells in tumors, given the absence of a native tumor microenvironment. Here, we used multiplexed single cell RNA-seq to profile ~200 cancer cell lines. We uncovered expression programs that are recurrently heterogeneous within many cancer cell lines and are largely independent of observed genetic diversity. These programs of heterogeneity are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial-to-mesenchymal transition, and protein maturation and degradation. Notably, some of these recurrent programs recapitulate those seen in human tumors, suggesting a prominent role of intrinsic plasticity in generating intra-tumoral heterogeneity. Moreover, the data allowed us to prioritize specific cell lines as model systems of cellular plasticity. We used two such models to demonstrate the dynamics, regulation and drug sensitivities associated with a cancer senescence program also observed in human tumors. Our work describes the landscape of cellular heterogeneity in diverse cancer cell lines, and identifies recurrent patterns of expression heterogeneity that are shared between tumors and specific cell lines and can thus be further explored in follow up studies.

cancer biology↗