title: 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.
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Chulmin
authors.initials: C
authors.lastname: Cho
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Ryen
authors.initials: R
authors.lastname: MacDonald
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Jijun
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Moon Jeong
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Lorraine E
authors.initials: LE
authors.lastname: Chalifour
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.|Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Paudel
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049229:Dendritic Spines / Q000502:physiology*; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D009479:Neuropeptides; C053386:drebrins
keywords: Egr-1; dendritic spine; drebrin