ARGLU1 is a Glucocorticoid Receptor Coactivator and Splicing Modulator Important in Stress Hormone Signaling and Brain Development

2 Summary Prolonged exposure to glucocorticoid stress hormones precipitates mood and cognitive disorders. We identified arginine and glutamate rich 1 (ARGLU1) in a screen for new modulators of glucocorticoid signaling in the CNS. Biochemical studies found that the glutamate rich C-terminus coactivates the glucocorticoid receptor (GR) and the arginine rich N-terminus interacts with splicing factors and RNA. RNA-seq of neuronal cells ±siARGLU1found significant changes in the expression and alternative splicing of distinct genes involved in neurogenesis. Loss of ARGLU1 was embryonic lethal in mice, and knockdown in zebrafish caused neurodevelopmental and heart defects. Treatment with dexamethasone, a GR activator, also induced changes in the pattern of alternatively spliced genes, highlighting an underappreciated global mechanism of glucocorticoid action in neuronal cells. Thus, in addition to its basal role, ARGLU1 links glucocorticoid-mediated transcription and alternative splicing in neural cells, providing new avenues from which to investigate the molecular underpinnings of cognitive stress disorders. 3 Highlights  ARGLU1 is a new GR coactivator that is nuclear localized and highly expressed in the CNS.  Dexamethasone, a GR ligand, induces alternative splicing changes in neural cells that are ARGLU1-dependent.  ARGLU1 impacts two layers of gene regulation (transcription and alternative splicing) on largely mutually exclusive genes.  Loss of ARGLU1 is embryonic lethal in mice and knockdown in zebrafish causes heart and brain defects. Short Summary Stress hormones, such as cortisol, significantly alter developing and adult neurons by signaling through the glucocorticoid receptor. We identified ARGLU1 as a glucocorticoid-receptor coactivator and RNA binding protein implicated in the regulation of both transcription and alternative splicing in neuronal cells. Glucocorticoid treatment caused widespread changes in alternative splicing that were abrogated in the absence of ARGLU1. Our data support a critical role for ARGLU1 in both basal and glucocorticoid-mediated alternative splicing and transcription, processes important for neuronal development. 4 The glucocorticoid receptor (GR) plays a fundamental role in coordinating the transcriptional response to stress hormones, such as cortisol, and is essential for organismal development, glucose homeostasis and immune function (Kadmiel and Cidlowski, 2013). Chronic stress, or administration of glucocorticoid drugs, is known to impair working memory and precipitate the onset of neuropsychiatric disorders (Judd et al., 2014; Lupien et al., 2007). In the brain, GR is highly expressed in the hippocampus where it has been shown to play a central role in modulating the proliferation and differentiation of neural stem and progenitor cells (Fitzsimons et al., 2016; …