During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain growth at the expense of other organs. In Drosophila, such brain sparing relies on a glia-derived growth factor to sustain proliferation of neural stem cells. However, whether other aspects of neural development are also spared under nutrient restriction is unknown. Here we show that dynamically growing somatosensory neurons in the Drosophila peripheral nervous system exhibit organ sparing at the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to neighboring non-neural tissues, resulting in dendrite overgrowth. These neurons express lower levels of the stress sensor FoxO than neighboring epidermal cells, and hence exhibit no marked induction of autophagy and a milder suppression of Tor signaling under nutrient stress. Preferential dendrite growth allows for heightened animal responses to sensory stimuli, indicative of a potential survival advantage under environmental challenges.

Astrocytes respond to injury, infection, and inflammation in the central nervous system by acquiring reactive states in which they may become dysfunctional and contribute to disease pathology. A sub-state of reactive astrocytes induced by proinflammatory factors TNF, IL-1α, and C1q (“TIC”) has been implicated in many neurodegenerative diseases as a source of neurotoxicity. Here, we used an established human induced pluripotent stem cell (hiPSC) model to investigate the surface marker profile and proteome of TIC-induced reactive astrocytes. We propose VCAM1, BST2, ICOSL, HLA-E, PD-L1, and PDPN as putative, novel markers of this reactive sub-state. We found that several of these markers colocalize with GFAP+ cells in post-mortem samples from people with Alzheimer’s disease. Moreover, our whole-cells proteomic analysis of TIC-induced reactive astrocytes identified proteins and related pathways primarily linked to potential engagement with peripheral immune cells. Taken together, our findings will serve as new tools to purify reactive astrocyte subtypes and to further explore their involvement in immune responses associated with injury and disease.

Phagocytic clearance of degenerating neurons is triggered by “eat-me” signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine (PS) and the engulfment receptor Draper (Drpr) mediate phagocytosis of degenerating neurons in Drosophila . However, how PS is recognized by Drpr-expressing phagocytes in vivo remains poorly understood. Using multiple models of dendrite degeneration, we show that the Drosophila chemokine–like protein Orion can bind to PS and is responsible for detecting PS exposure on neurons; it is supplied cell-non-autonomously to coat PS-exposing dendrites and to mediate interactions between PS and Drpr, thus enabling phagocytosis. As a result, the accumulation of Orion on neurons and on phagocytes produces opposite outcomes by potentiating and suppressing phagocytosis, respectively. Moreover, the Orion dosage is a key determinant of the sensitivity of phagocytes to PS exposed on neurons. Lastly, mutagenesis analyses show that the sequence motifs shared between Orion and human immunomodulatory proteins are important for Orion function. Thus, our results uncover a missing link in PS-mediated phagocytosis in Drosophila and imply conserved mechanisms of phagocytosis of neurons.

Phagocytic clearance of degenerating neurons is mediated by "eat-me" signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine (PS) is detected by resident phagocytes through specialized recognition systems. The engulfment receptor Draper (Drpr) is known to mediate PS recognition in Drosophila. However, how Drpr recognizes PS in vivo is unclear. Using larval dendritic arborization (da) neurons and phagocytic epidermal cells as a model, we show that the recently discovered Drosophila chemokine-like Orion is the responsible PS sensor; it functions as a cell-non-autonomous bridging molecule between PS and Drpr to license phagocytosis. Moreover, the Orion dosage is a key determinant of the sensitivity of phagocytes to PS exposed on neurons. Lastly, mutagenesis analysis reveals evolutionarily conserved sequence motifs that are important for Orion secretion and binding to PS. Thus, our results uncover a missing link in PS-mediated phagocytosis in Drosophila and imply conserved mechanisms of phagocytosis of neurons.

17During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain 18 growth at the expense of other organs. In Drosophila, such brain sparing relies on a glia-derived growth 19 factor to sustain proliferation of neural stem cells. However, whether other aspects of neural 20 development are also spared under nutrient restriction is unknown. Here we show that dynamically 21 growing somatosensory neurons in the Drosophila peripheral nervous system exhibit organ sparing at 22 the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to 23 neighboring non-neural tissues, resulting in dendrite overgrowth. Underlying this neuronal nutrient-24 insensitivity is the lower expression of the stress sensor FoxO in neurons. Consequently, nutrient 25 restriction suppresses Tor signaling less and does not induce autophagy in neurons. Preferential dendrite 26 growth is functional desirable because it results in heightened animal responses to sensory stimuli, 27 indicative of a potential survival advantage under environmental challenges.28