NEUROD2 Regulates Stim1 Expression and Store-Operated Calcium Entry in Cortical Neurons

Abstract Calcium signaling controls many key processes in neurons, including gene expression, axon guidance, and synaptic plasticity. In contrast to calcium influx through voltage- or neurotransmitter-gated channels, regulatory pathways that control store-operated calcium entry (SOCE) in neurons are poorly understood. Here, we report a transcriptional control of Stim1 (stromal interaction molecule 1) gene, which is a major sensor of endoplasmic reticulum (ER) calcium levels and a regulator of SOCE. By using a genome-wide chromatin immunoprecipitation and sequencing approach in mice, we find that NEUROD2, a neurogenic transcription factor, binds to an intronic element within the Stim1 gene. We show that NEUROD2 limits Stim1 expression in cortical neurons and consequently fine-tunes the SOCE response upon depletion of ER calcium. Our findings reveal a novel mechanism that regulates neuronal calcium homeostasis during cortical development. Significance Statement Store-operated calcium entry (SOCE) is a major source of neuronal calcium influx. Although SOCE controls key neurodevelopmental processes, the gene expression programs that regulate this mode of calcium entry in neurons remain poorly understood. In this study, we conducted an in vivo genome-wide target gene analysis of the neurogenic transcription factor NEUROD2. We find that NEUROD2 controls the Stim1 gene, which encodes a major ER calcium sensor and an essential component of SOCE. Consequently, we demonstrate that NEUROD2 is a critical regulator of neuronal SOCE levels. Our findings present important implications for understanding transcriptional programs that control neuronal calcium homeostasis, as well as for disease mechanisms in which deranged SOCE is observed, such as epilepsy and Alzheimer’s disease.