title: Integration of CNS survival and differentiation by HIF2α.
abstract: Hypoxia-inducible factor (HIF) 1α and HIF2α and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the central nervous system; however, little is known about their functions in embryos. Here, we show that zebrafish HIF2α protects neural progenitor cells and neural differentiation processes by upregulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2α reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2α morphants. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2α. Chromatin immunoprecipitation assay revealed that HIF2α binds to birc5a and birc5b promoters directly to modulate their transcriptions. Knockdown of hif2α, birc5a or birc5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2α morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2α depletion is due in part to the loss of survivin activity.
authors.affiliation: Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan, ROC.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Ko
authors.forename: M-Y
authors.initials: MY
authors.lastname: Tsai
authors.forename: W-F
authors.initials: WF
authors.lastname: Tseng
authors.forename: C-H
authors.initials: CH
authors.lastname: Cheng
authors.forename: C-R
authors.initials: CR
authors.lastname: Huang
authors.forename: J-S
authors.initials: JS
authors.lastname: Wu
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chung
authors.forename: C-S
authors.initials: CS
authors.lastname: Hsieh
authors.forename: C-K
authors.initials: CK
authors.lastname: Sun
authors.forename: S-P L
authors.initials: SP
authors.lastname: Hwang
authors.forename: C-H
authors.initials: CH
authors.lastname: Yuh
authors.forename: C-J
authors.initials: CJ
authors.lastname: Huang
authors.forename: T-W
authors.initials: TW
authors.lastname: Pai
authors.forename: W-S
authors.initials: WS
authors.lastname: Tzou
authors.forename: C-H
authors.initials: CH
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002490:Central Nervous System / Q000166:cytology*; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D004625:Embryo, Nonmammalian; D047108:Embryonic Development; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060172:Morpholinos / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013234:Stem Cells / Q000166:cytology; D000077022:Survivin; D015854:Up-Regulation; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D060172:Morpholinos; D000077022:Survivin; D029961:Zebrafish Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C541681:Birc5a protein, zebrafish; C540300:Birc5b protein, zebrafish