Early growth response‐1‐mediated down‐regulation of drebrin correlates with loss of dendritic spines

Abstract

Post-synaptic dendritic spines are structurally composed of actin cytoskeleton, which undergoes dynamic morphological changes to accommodate incoming synaptic activity. Drebrin is an actin-binding protein highly expressed in dendritic spines that serves an important role in regulating spine morphology. Functionally, loss of drebrin directly correlates with deficits in learning and memory, as is the case observed in Alzheimer's disease. Despite these findings, the regulatory factor responsible for drebrin loss remains unclear. Here, we show that early growth response-1 (Egr-1), an inducible zinc finger transcription factor, down-regulates drebrin expression. Chromatin immunoprecipitation analyses identified Egr-1 binding sites upstream of the drebrin start site in neuronal cells. Over-expression of Egr-1 in vitro in primary hippocampal neurons or in vivo in homogenates prepared from the hippocampi of an inducible mouse model of Egr-1 show reduced drebrin mRNA and protein levels. Conversely, increased drebrin was detected in hippocampal samples isolated from Egr-1-deficient brain. These data demonstrate that Egr-1 interacts with the drebrin promoter and negatively regulates drebrin expression. Furthermore, immunocytochemical and Golgi staining analyses revealed reduced drebrin protein and dendritic spine density as well as reduced expression of synaptic markers in in vitro hippocampal neurons over-expressing Egr-1 and in vivo inducible mouse model of Egr-1. In contrast, increased drebrin expression correlated with increased dendritic spine density was detected in samples from Egr-1-deficient mice. These data provide evidence that Egr-1 is a novel regulator of drebrin expression, which is linked to changes in dendritic spine density.

A Novel Egr-1-Agrin Pathway and Potential Implications for Regulation of Synaptic Physiology and Homeostasis at the Neuromuscular Junction

“…Egr-1 is activated rapidly in response to many different factors, including neural activity and neurotransmission, growth factors, cytokines, pharmacological agents, stimulation, stress, and DNA damage, among others, indicating that Egr-1 is involved in a multitude of physiological processes and regulates many different synapse-associated genes (Gashler and Sukhatme, 1995 ; Beckmann and Wilce, 1997 ; O’Donovan et al, 1999 ; Clayton, 2000 ; James et al, 2005 ; Pagel and Deindl, 2011 ). In addition to agrin regulation as described in this study, Egr-1 also influences the expression and regulation of the plasticity related Arc gene, as well as SNARE, synapsin II, serpine I, galectin-3 binding protein, integrin associated protein (IAP), cystatin c, PSD95, Shank3, neuronal specific septin 3, s100B, phospholipase C, protein kinase C, BACE1 and drebrin among several others (James et al, 2005 ; Li et al, 2005 ; Baumgärtel et al, 2009 ; Qin et al, 2016 ; Cho et al, 2017 ). Thus, Egr-1 may have direct targets in addition to, or other than, agrin, which may contribute to or cause the noted changes of Egr-1−/− mice compared with WT, as seen in this study.…”

Neuritin promotes neurite and spine growth in rat cerebellar granule cells via L‐type calcium channel‐mediated calcium influx

“…Neurite lengths and branches of selected cells were reconstructed using NIH ImageJ software (RRID:SCR_003070) (Cho et al . ). Sholl analysis was carried out to quantify the number of branch intersections (Yao et al .…”

Drebrin 1 in dendritic cells regulates phagocytosis and cell surface receptor expression through recycling for efficient antigen presentation

“…The protein plays a significant role in increasing filament stiffness through direct binding interactions . Dbn1 therefore has a critical role in neuronal dendrite cell spine morphogenesis, synaptogenesis, synaptic plasticity, cell migration, communication, and differentiation . In myeloid cells, inhibition of Dbn1 impairs actin cytoskeleton reorganization and Ca 2+ influx, resulting in impaired Fc ε RI‐mediated degranulation and histamine release in mast cells .…”

“…9 Dbn1 therefore has a critical role in neuronal dendrite cell spine morphogenesis, synaptogenesis, synaptic plasticity, cell migration, communication, and differentiation. [10][11][12] In myeloid cells, inhibition of Dbn1 impairs actin cytoskeleton reorganization and Ca 2+ influx, resulting in impaired FceRI-mediated degranulation and histamine release in mast cells. 13. Although Dbn1 has been shown to have functional roles in lymphocytes and mast cells, the role of Dbn1 in DC antigen presentation and innate immunity is unknown.…”