title: Transcriptional Profiling of Hypoxic Neural Stem Cells Identifies Calcineurin-NFATc4 Signaling as a Major Regulator of Neural Stem Cell Biology.
abstract: Neural stem cells (NSCs) reside in a hypoxic microenvironment within the brain. However, the crucial transcription factors (TFs) that regulate NSC biology under physiologic hypoxia are poorly understood. Here we have performed gene set enrichment analysis (GSEA) of microarray datasets from hypoxic versus normoxic NSCs with the aim of identifying pathways and TFs that are activated under oxygen concentrations mimicking normal brain tissue microenvironment. Integration of TF target (TFT) and pathway enrichment analysis identified the calcium-regulated TF NFATc4 as a major candidate to regulate hypoxic NSC functions. Nfatc4 expression was coordinately upregulated by top hypoxia-activated TFs, while NFATc4 target genes were enriched in hypoxic NSCs. Loss-of-function analyses further revealed that the calcineurin-NFATc4 signaling axis acts as a major regulator of NSC self-renewal and proliferation in vitro and in vivo by promoting the expression of TFs, including Id2, that contribute to the maintenance of the NSC state.
authors.affiliation: Clinical and Experimental Neurosciences, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Fernández
authors.affiliation: Clinical and Experimental Neurosciences, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Monllau
authors.affiliation: Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Borrell
authors.affiliation: Endocrinology, Hospital Sant Joan de Déu, 08950 Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Lerin
authors.affiliation: Clinical and Experimental Neurosciences, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain. Electronic address: niglesia@clinic.ub.es.
authors.forename: Núria
authors.initials: N
authors.lastname: de la Iglesia
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; D019703:Calcineurin; D010100:Oxygen