Glia-Derived Upd1 Promotes Dendritic Remodeling via Neuronal JAK/STAT-CK2α Signaling

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Neural pruning optimizes the structure of neural circuits by selectively eliminating redundant or weakened synaptic connections, thereby enhancing the precision and efficiency of information transmission. Dendrites of class IV dendritic arborization (C4da) sensory neurons of Drosophila undergo a large-scale pruning process during development. However, it is currently ambiguous whether peripheral glia non-cell-autonomously modulate dendritic pruning in C4da neurons by transmitting signals. Here, we show that Unpaired1 (Upd1), a secreted glycoprotein, acts as a glial-originated signaling molecule to promote dendritic pruning during development in both male and female Drosophila . Our further investigation reveals that downregulation of Domeless (Dome), the receptor of Upd1, in C4da neurons also triggers dendritic pruning defects. Hopscotch (Hop) kinase and transcription factor Stat92E, as downstream factors activated by Upd1 and Dome, similarly facilitate dendritic pruning. Notably, the Upd1 deficiency in glia produces a significant diminishment in JAK/STAT activity, and reactivation of this signaling in C4da neurons alleviates the dendritic pruning phenotype caused by glial Upd1 deficits. Furthermore, casein kinase II alpha (CK2α), the catalytic subunit of the serine/threonine protein kinase CK2, acts as a downstream target of the JAK/STAT and contributes to dendritic pruning. Collectively, we reveal a novel mechanism by which glia-derived Upd1 promotes dendritic pruning in C4da neurons by interacting with neuronal receptor Dome and activating the JAK/STAT signaling and downstream CK2α. Significance Statement Neural circuits are refined during development by selectively removing unnecessary branches and connections, but whether neighboring glia control this process via intercellular signaling remains not fully understood. Using Drosophila sensory neurons, we show that glia release the signaling protein Unpaired1 (Upd1), which activates neuronal JAK/STAT signaling to promote dendritic pruning. Restoring this pathway in neurons alleviates pruning defects caused by glial Upd1 deficiency, and we identify casein kinase CK2α as a downstream mediator. By revealing a glia-to-neuron signaling mechanism that coordinates developmental dendrite remodeling, this study expands our understanding of how neural circuits are refined during development and provides a conceptual basis for investigating how disrupted glial signaling and aberrant pruning may contribute to neurodevelopmental disorders.

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