Highlights d Single-cell RNA-seq reveals two distinct B cell lineages d An alternative lineage contains CXCR3 + and atypical B cells d Alternative B cells are primed after primary vaccination and respond to boosters d Alternative B cells adopt a more atypical phenotype following repeated antigen exposure

Early growth response (Egr) transcription factors (Egr1 to Egr4) are synaptic activity-inducible immediate early genes (IEGs) that regulate some aspects of synaptic plasticity-related to learning and memory, yet the target genes regulated by them are unknown. In particular, Egr1 is essential for persistence of late-phase long-term potentiation (L-LTP), for hippocampus-dependent long-term memory formation, and for reconsolidation of previously established memories. Here, we show that Egr1 and Egr3 directly regulate the plasticityassociated activity-regulated cytoskeletal-related (Arc) gene, a synaptic activity-induced effector molecule which is also required for L-LTP and hippocampus-dependent learning and memory processing. Moreover, Egr1-deficient and Egr3-deficient mice lack Arc protein in a subpopulation of neurons, while mice lacking both Egr1 and Egr3 lack Arc in all neurons. Thus, Egr1 and Egr3 can indirectly modulate synaptic plasticity by directly regulating Arc and the plasticity mechanisms it mediates in recently activated synapses.

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Vertebrate muscle spindle stretch receptors are important for limb position sensation (proprioception) and stretch reflexes. The structurally complex stretch receptor arises from a single myotube, which is transformed into multiple intrafusal muscle fibers by sensory axon–dependent signal transduction that alters gene expression in the contacted myotubes. The sensory-derived signal transduction pathways that specify the fate of myotubes are very poorly understood. The zinc finger transcription factor, early growth response gene 3 (Egr3), is selectively expressed in sensory axon–contacted myotubes, and it is required for normal intrafusal muscle fiber differentiation and spindle development. Here, we show that overexpression of Egr3 in primary myotubes in vitro leads to the expression of a particular repertoire of genes, some of which we demonstrate are also regulated by Egr3 in developing intrafusal muscle fibers within spindles. Thus, our results identify a network of genes that are regulated by Egr3 and are involved in intrafusal muscle fiber differentiation. Moreover, we show that Egr3 mediates myotube fate specification that is induced by sensory innervation because skeletal myotubes that express Egr3 independent of other sensory axon regulation are transformed into muscle fibers with structural and molecular similarities to intrafusal muscle fibers. Hence, Egr3 is a target gene that is regulated by sensory innervation and that mediates gene expression involved in myotube fate specification and intrafusal muscle fiber morphogenesis.

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