title: Presenilins regulate neurotrypsin gene expression and neurotrypsin-dependent agrin cleavage via cyclic AMP response element-binding protein (CREB) modulation.
abstract: Presenilins, the catalytic components of the γ-secretase complex, are upstream regulators of multiple cellular pathways via regulation of gene transcription. However, the underlying mechanisms and the genes regulated by these pathways are poorly characterized. In this study, we identify Tequila and its mammalian ortholog Prss12 as genes negatively regulated by presenilins in Drosophila larval brains and mouse embryonic fibroblasts, respectively. Prss12 encodes the serine protease neurotrypsin, which cleaves the heparan sulfate proteoglycan agrin. Altered neurotrypsin activity causes serious synaptic and cognitive defects; despite this, the molecular processes regulating neurotrypsin expression and activity are poorly understood. Using γ-secretase drug inhibitors and presenilin mutants in mouse embryonic fibroblasts, we found that a mature γ-secretase complex was required to repress neurotrypsin expression and agrin cleavage. We also determined that PSEN1 endoproteolysis or processing of well known γ-secretase substrates was not essential for this process. At the transcriptional level, PSEN1/2 removal induced cyclic AMP response element-binding protein (CREB)/CREB-binding protein binding, accumulation of activating histone marks at the neurotrypsin promoter, and neurotrypsin transcriptional and functional up-regulation that was dependent on GSK3 activity. Upon PSEN1/2 reintroduction, this active epigenetic state was replaced by a methyl CpG-binding protein 2 (MeCP2)-containing repressive state and reduced neurotrypsin expression. Genome-wide analysis revealed hundreds of other mouse promoters in which CREB binding is similarly modulated by the presence/absence of presenilins. Our study thus identifies Tequila and neurotrypsin as new genes repressed by presenilins and reveals a novel mechanism used by presenilins to modulate CREB signaling based on controlling CREB recruitment.
authors.affiliation: From the Departments of Cellular and Molecular Medicine.
authors.forename: Angels
authors.initials: A
authors.lastname: Almenar-Queralt
authors.forename: Sonia N
authors.initials: SN
authors.lastname: Kim
authors.forename: Christopher
authors.initials: C
authors.lastname: Benner
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Herrera
authors.forename: David E
authors.initials: DE
authors.lastname: Kang
authors.forename: Ivan
authors.initials: I
authors.lastname: Garcia-Bassets
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
mesh_terms: D018171:Agrin / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053766:Presenilin-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018171:Agrin; D017362:Cyclic AMP Response Element-Binding Protein; D029721:Drosophila Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; C095101:Psen2 protein, mouse; C580804:presenilin 1, mouse; D053829:Amyloid Precursor Protein Secretases; D012697:Serine Endopeptidases; C512782:Teq protein, Drosophila; C108493:neurotrypsin
keywords: CREB; Chromatin Immunoprecipitation (ChIP); Drosophila Larval Brains; GSK3; MEFs; Neurotrypsin; Presenilin; Promoters; Secretases; Tequila