Biology subjects

Connolly, E. C.

Publications and source records attributed to Connolly, E. C..

5 recordsLinked to original sources

bioRxiv2026

Higher-Order Mechanical Neighbourhood Sensing Governs Cell Fate in Complex Tissues

Adult tissues maintain precise architectures composed of multiple interspersed cell types, yet prevailing models of cell fate patterning rely on pairwise interactions between neighbouring cells that generate binary decisions. How local interactions encode higher-order, beyond pairwise, multicellular organization remains unclear. Here, using the Drosophila midgut as a model of adult tissue self-organization, we identify a higher-order neighbourhood-sensing mechanism that couples cell identity, mechanics and stem cell (SC) fate. We show that the receptors Cirl/Latrophilin and Toll-8 are expressed in complementary cellular compartments, restricting their engagement to heterotypic interfaces between progenitors and differentiated enterocytes (ECs). These interactions generate interface-specific myosin II-dependent tension that depends on EC neighbourhood composition and mechanically gates Delta-Notch signalling. Thus, although Delta-Notch acts through pairwise interactions, these fate decisions are modulated by a higher-order mechanical state integrating information from surrounding cell contacts. A mathematical model incorporating this coupling reproduces multicellular tissue architecture from first principles and predicts that loss of higher-order coupling destabilizes progenitor organization. This prediction is consistent with the excessive fate transitions, topological disorganization and regenerative defects observed after Cirl-Toll-8 disruption. These findings establish higher-order mechanical neighbourhood sensing as a general principle by which tissues integrate local cellular identities to maintain and restore complex architectures.

cell biology↗

bioRxiv2026

Weckle is a molecular switch that diverts Toll signalling from innate immunity towards growth by engaging Yki

The mechanisms underlying how the brain can switch from a plastic to a degenerative state are unknown. Tolls and Toll-Like receptors (TLRs) could be involved since they underlie both neuroinflammation and structural brain plasticity. Here, we show that the Toll signalling adaptor Weckle (Wek) - a ZAD-Zinc-finger transcription factor - can switch the response from promoting innate immunity or cell death, to inducing growth instead. Myristoylated Wek binds Tolls at the membrane, and concerted PI3K and Toll signalling drive its nuclear translocation. Wek interacts with Yorkie (Yki) - the key regulator of growth restrained by Hippo - enabling its nuclear shuttling. Remarkably, Wek blocks innate immunity. Instead, Wek and Yki together drive glial cell proliferation and growth. Through this mechanism, Toll signalling could promote structural brain plasticity via Wek and Yki downstream. As Tolls and Yki are widespread, these findings could have important implications for understanding also regeneration and cancer.

developmental biology↗

bioRxiv2024

Glia-mediated gut-brain cytokine signaling couples sleep to intestinal inflammation

Sickness-induced sleep is a behavior conserved across species that promotes recovery from illness, yet the underlying mechanisms are poorly understood. Here, we show that interleukin-6-like cytokine signaling from the Drosophila gut to brain glial cells regulates sleep. Under healthy conditions, this pathway promotes wakefulness. However, elevated gut cytokine signaling in response to oxidative stress - triggered by immune and inflammatory responses in the intestine - induces sleep. The cytokines Unpaired 2 and -3 are upregulated by oxidative stress in enteroendocrine cells and activate JAK-STAT signaling in glial cells, including those of the blood-brain barrier (BBB). This activity maintains elevated sleep during oxidative-stress-induced intestinal disturbances, suggesting that the JAK-STAT pathway in glia inhibits wake-promoting signaling to facilitate sleep-dependent restoration under these conditions. We find that the enteric peptide Allatostatin A (AstA) enhances wakefulness, and during intestinal oxidative stress, gut-derived Unpaired 2/3 inhibits AstA receptor expression in BBB glia, thereby sustaining an elevated sleep state during gut inflammation or illness. Taken together, our work identifies a gut-to-glial communication pathway that couples sleep with intestinal homeostasis and disease, enhancing sleep during intestinal sickness, and contributes to our understanding of how sleep disturbances arise from gastrointestinal disturbances.

animal behavior and cognition↗

bioRxiv2024

UPF1 is required for gene expression in mitochondria and for the elimination of paternal mtDNA

UPF1 is a conserved RNA helicase in eukaryotes typically defined by its role in nonsense-mediated mRNA decay (NMD). This study presents ChIP-seq evidence indicating an RNA-dependent interaction of UPF1 with mtDNA, consistent with an RNA-mediated association. Mitochondrial localisation was observed as discrete foci throughout the mitochondrial network, frequently in proximity to nucleoids, as confirmed microscopically by immunostaining and GFP tagging of UPF1 in different fly tissues and S2 cells. Depletion of UPF1, but not depletion of the other core NMD factors UPF2 or UPF3, in salivary glands results in smaller mitochondria and, unexpectedly, increased respiratory activity. This increase is observed specifically in salivary glands and correlates with elevated expression of nuclear genes involved in respiratory chain assembly and mitochondrial translation. Changes in mtDNA-encoded gene expression are also observed upon the depletion of UPF1. These findings indicate that UPF1 operates in mitochondria and, independently of canonical NMD, is linked to mitochondrial gene expression and may coordinate nuclear and mitochondrial gene expression in a tissue-specific manner.

cell biology↗

bioRxiv2020

A temporal map of maternal immune activation-induced changes reveals a shift in neurodevelopmental timing and perturbed cortical development in mice.

BackgroundEnvironmental insults that activate the maternal immune system are potent primers of developmental neuropathology and maternal immune activation (MIA) has emerged as a risk factor for neurodevelopmental and psychiatric disorders. Animal models of MIA provide an opportunity to identify molecular pathways that initiate disease processes and lead to neuropathology and behavioral deficits in offspring. MIA-induced behaviors are accompanied by anatomical and neurochemical alterations in adult offspring that parallel those seen in affected human populations. MethodsWe performed transcriptional profiling and neuroanatomical characterization in a time course across mouse embryonic cortical development, following MIA via single injection of the viral mimic polyinosinic:polycytidylic acid (polyI:C) at E12.5. Transcriptional changes identified in the cortex of MIA offspring at E17.5 were validated and mapped to cortical neuroanatomy and cell types via protein analysis and immunohistochemistry. ResultsMIA induced strong transcriptomic signatures, including induction of genes associated with hypoxia, immune signaling, and angiogenesis. The acute response identified 6h after the MIA insult was followed by changes in proliferation, neuronal and glial differentiation, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cell types in germinal zones and alterations in neuronal and glial cell types across cortical lamina were identified in the MIA-exposed cortex. ConclusionsMIA-induced transcriptomic signatures in fetal offspring overlap significantly with perturbations identified in neurodevelopmental disorders (NDDs), and provide novel insights into alterations in molecular and developmental timing processes linking MIA and neuropathology, potentially revealing new targets for development of novel approaches for earlier diagnosis and treatment of these disorders.

neuroscience↗