Neuronal synapse formation and remodeling is essential to central nervous system (CNS) development and is dysfunctional in neurodevelopmental diseases. Innate immune signals regulate tissue remodeling in the periphery, but how this impacts CNS synapses is largely unknown. Here we show that the IL-1 family cytokine Interleukin-33 (IL-33) is produced by developing astrocytes and is developmentally required for normal synapse numbers and neural circuit function in the spinal cord and thalamus. We find that IL-33 signals primarily to microglia under physiologic conditions, that it promotes microglial synapse engulfment, and that it can drive microglial-dependent synapse depletion in vivo. These data reveal a cytokine-mediated mechanism required to maintain synapse homeostasis during CNS development.

Highlights d IL-33 is expressed by subsets of hippocampal neurons and is modulated by experience d Microglia drive dendritic spine plasticity and memory precision via neuronal IL-33 d IL-33 gain of function mitigates some age-related decreases in spine plasticity d Neuronal IL-33 induces microglial remodeling of the extracellular matrix

Daley and collaborators show that endogenous Lin28b drives erythroid-dominant fetal hematopoiesis and that decreases in Lin28b activate adult granulocyte-predominant hematopoiesis.

Key Points Combining flow cytometry and high-performance mass spectrometry enables phosphoproteomic analysis of rare blood cell populations. ARHGAP25 dephosphorylation augments activity and promotes blood stem and progenitor cell mobilization by enhancing CXCL12 and Rac signaling.